JP2018510138A - Inhibition of OLIG2 activity - Google Patents

Abstract

Described herein are compounds that inhibit Olig2 activity and pharmaceutical compositions comprising the compounds. Further described herein are methods of using Olig2 inhibitors as described above alone or in combination with other compounds to treat cancer and other diseases. In particular, Olig2 inhibitors may be used to treat glioblastoma. [Selection figure] None

Description

<Related applications>
This application claims the benefit of priority from US Provisional Application No. 62 / 126,382, filed February 27, 2015, which is hereby incorporated by reference in its entirety. .

  Modern brain tumor treatments can only extend the median survival of patients by 6 months and cause enormous systemic toxicity. This toxicity causes severe long-term morbidity in the few patients who survive in terms of cognition, endocrine disorders, and motor effects. Currently, brain tumors are essentially incurable with a median survival of 15 months.

  As used herein, for the inhibition of Olig2 activity, the formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), Or a compound of (VI) (hereinafter “formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or Compounds of (VI))), compositions containing the above compounds and methods of their use are described.

  In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein,

Where
A is a single bond, O, or N (R ₁₀ );
X, Y, and Z are each independently N or C (R ₇ ), and at least one of X, Y, and Z is N;
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ ,-(C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), or

And
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
J is C (H) or N;
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
Each R ₇ is independently H, halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ Alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C _6- be a C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H, or unsubstituted C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-5,
p is 1-3;
q is 1-3.

In one embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, There are compounds of (I). In another embodiment are compounds of formula (I) wherein R ₂ and R ₃ are each H. In another embodiment are compounds of formula (I), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (I), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment are compounds of formula (I), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In a further embodiment are compounds of formula (I), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment, R ₆ is

There are compounds of formula (I) In another embodiment are compounds of formula (I) wherein R ₁₃ is H. In another embodiment are compounds of formula (I), wherein R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (I), wherein R ₁₃ is —CH ₃ . In another embodiment are compounds of formula (I), wherein R ₁₃ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (I), wherein J is C (H). In another embodiment are compounds of formula (I) wherein p is 2 and q is 1. In another embodiment are compounds of formula (I) wherein p is 3 and q is 1. In another embodiment are compounds of formula (I) wherein p is 2 and q is 2. In another embodiment of the aforementioned embodiments are compounds of formula (I) wherein J is N. In another embodiment are compounds of formula (I) wherein p is 2 and q is 2. In another embodiment of the foregoing embodiments, there is a compound of formula (I), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment of the foregoing embodiments are compounds of formula (I), wherein R ₆ is substituted or unsubstituted morpholinyl. In another embodiment of the foregoing embodiments are compounds of formula (I) wherein R ₆ is a substituted or unsubstituted piperidinyl. In another embodiment of the foregoing embodiments, there is a compound of formula (I), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment of the foregoing embodiments, there is a compound of formula (I), wherein R ₂₁ is —OH. In another embodiment of the foregoing embodiments are compounds of formula (I), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment of the foregoing embodiments are compounds of formula (I), wherein R ₁₁ and R ₁₂ are each CH ₃ . In another embodiment of the foregoing embodiments are compounds of formula (I) wherein R ₁₄ and R ₁₅ are each H. In another embodiment of the aforementioned embodiments are compounds of formula (I) wherein m is 2. In another embodiment of the foregoing embodiments are compounds of formula (I) wherein m is 3. In another embodiment of the aforementioned embodiments are compounds of formula (I) wherein A is N (R ₁₀ ). In another embodiment are compounds of formula (I), wherein R ₁₀ is H or CH ₃ . In another embodiment of the foregoing embodiments are compounds of formula (I) wherein A is O. In another embodiment of the aforementioned embodiments are compounds of formula (I) wherein A is a single bond. In another embodiment of the foregoing embodiments are compounds of formula (I), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (I), wherein R ₅ is CH ₃ . In another embodiment are compounds of formula (I), wherein R ₅ is CH ₂ CH ₃ . In another embodiment of the aforementioned embodiments are compounds of formula (I) wherein n is 2. In another embodiment of the foregoing embodiments are compounds of formula (I) wherein n is 1. In another embodiment of the foregoing embodiments are compounds of formula (I) wherein n is 0. In another embodiment of the foregoing embodiments, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted Substituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted Or a compound of formula (I), which is unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. There are compounds of formula (I) In another embodiment of the foregoing, there are compounds of formula (I), wherein two R ₁ together form a substituted or unsubstituted heterocycle, or a substituted or unsubstituted cyclic carbon. In another embodiment of the foregoing embodiments are compounds of formula (I), wherein X is C (R) ₇ , Y is N, and Z is N. In another embodiment of the foregoing embodiments are compounds of formula (I) wherein X is C (R) ₇ , Y is C (R) ₇ , and Z is N. In another embodiment of the foregoing embodiments are compounds of formula (I) wherein X is C (R) ₇ , Y is N, and Z is C (R) ₇ . In another embodiment of the foregoing embodiments, a compound of formula (I) wherein X is C (R) ₇ , Y is C (R) ₇ , and Z is C (R) ₇ is is there. In another embodiment of the aforementioned embodiments are compounds of formula (I) wherein R ₇ is H. In another embodiment of the foregoing embodiments are compounds of formula (I) wherein X is N, Y is N, and Z is N.

  In another aspect, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein,

Where
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , or

And
J is C (H),
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C, ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H, or unsubstituted C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-5,
p is 1-3;
q is 1-3.

In one embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There is a compound of (II). In another embodiment are compounds of formula (II), wherein R ₂ and R ₃ are each H. In another embodiment are compounds of formula (II), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (II), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment of the aforementioned embodiments, R ₂₁ is —OH, —N (R ₂₂ ) S (═O) ₂ R ₂₃ , —CO ₂ R ₂₂ , —C (═O) N (R ₂₂ ) _{2. , -N (R 22) C (} = O) R 23, a substituted or unsubstituted _C 1 -C ₆ alkoxy, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, a compound of formula (II) is there. In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₂₁ is —OH. In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₂₁ is —N (R ₂₂ ) S (═O) ₂ R ₂₃ . In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₂₁ is —N (R ₂₂ ) C (═O) R ₂₃ . In a further embodiment are compounds of formula (II), wherein R ₂₁ is —N (R ₂₂ ) S (═O) ₂ R ₂₃ . In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₂₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment of the foregoing embodiments, each R ₂₂ is independently H, or unsubstituted C ₁ -C ₆ alkyl, and R ₂₃ is unsubstituted C ₁ -C ₆ alkyl. There is a compound of formula (II). In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₁₄ and R ₁₅ are each H. In another embodiment of the foregoing embodiments are compounds of formula (II) wherein m is 2. In another embodiment of the foregoing embodiments are compounds of formula (II) wherein m is 3. In another embodiment are compounds of formula (II), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In a further embodiment are compounds of formula (II), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment of the foregoing embodiments are compounds of formula (II), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₆ is substituted or unsubstituted morpholinyl. In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₆ is substituted or unsubstituted piperidinyl. In another embodiment are compounds of formula (II), wherein R ₁₀ is H or CH ₃ .

  In another aspect, a compound of formula (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein,

Where
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (═O) _2. R ₉ , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO ₂ R ₈ , _{-N (R 8) 2, -C} (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted Substituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, Or, two R ₁ s together, form a substituted or unsubstituted heterocyclic or substituted or unsubstituted ring carbon,
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₄ is H, halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (═O) ₂ R _9. , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl substituted, or a substituted or unsubstituted _C 2 -C ₇ heteroaryl, or 2 The of R ₁ together, a substituted or unsubstituted heterocyclic ring, or form a substituted or unsubstituted carbocyclic ring, wherein, when n is 0, R ₄ is not a halogen,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ),
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H or C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-4.

In one embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There is a compound of (IIA). In another embodiment are compounds of formula (IIA), wherein R ₂ and R ₃ are each H. In another embodiment are compounds of formula (IIA), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (IIA), wherein R ₂ and R ₃ are joined to form a 5-membered heterocycle. In another embodiment of the foregoing embodiments, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), and R ₁₄ and R ₁₅ are each H. There are compounds of formula (II). In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment of the foregoing embodiments, there are compounds of formula (II), wherein R ₁₁ and R ₁₂ are each independently unsubstituted C ₁ -C ₆ alkyl. In another embodiment of the foregoing embodiments, there is a compound of formula (II), wherein R ₁₁ and R ₁₂ are each —CH ₃ . In another embodiment of the foregoing embodiments are compounds of formula (II) wherein m is 2. In another embodiment of the foregoing embodiments are compounds of formula (II) wherein m is 3. In another embodiment are compounds of formula (II), wherein R ₁₀ is H or CH ₃ . In another embodiment of the foregoing embodiments are compounds of formula (II) wherein n is 0. In another embodiment of the aforementioned embodiments are compounds of formula (II) wherein n is 1.

  In another aspect, a compound of formula (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein:

Where
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H or C ₁ -C ₄ alkyl, or R ₂ and R ₃ together form a 5- or 6-membered heterocycle,
R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₆ is unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , or

And
J is C (H),
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, halogen, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H;
m is 2-6,
n is 0-5,
p is 1-3;
q is 1-3.

In some embodiments, there is a compound of formula (VI), wherein R ₂ and R ₃ are each independently H or C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (VI), wherein R ₂ and R ₃ are each H. In another embodiment are compounds of formula (VI), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (VI), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment are compounds of formula (VI), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment are compounds of formula (VI), wherein R ₁₄ and R ₁₅ are each independently H, halogen, or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (VI), wherein R ₁₄ and R ₁₅ are each H. In another embodiment, R ₂₁ is —OH, —N (R ₂₂ ) S (═O) ₂ R ₂₃ , —CO ₂ R ₂₂ , —C (═O) N (R ₂₂ ) ₂ , —N (R ₂₂₎ a C (= _{O) R 23,} substituted or unsubstituted _C 1 -C ₆ alkoxy, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, are the compounds of formula (VI). In another embodiment of the foregoing embodiments, there is a compound of formula (VI), wherein R ₂₁ is —OH. In another embodiment of the foregoing embodiments, there is a compound of formula (VI), wherein R ₂₁ is —N (R ₂₂ ) S (═O) ₂ R ₂₃ . In another embodiment of the foregoing embodiments, there is a compound of formula (VI), wherein R ₂₁ is —N (R ₂₂ ) C (═O) R ₂₃ . In a further embodiment, R ₂₁ is —N (R ₂₂ ) S (═O) ₂ R ₂₃ . In another embodiment of the foregoing embodiments, there is a compound of formula (VI), wherein R ₂₁ is a substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment of the foregoing embodiments are compounds of formula (VI), wherein R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each of R ₂₂ is independently H, or unsubstituted C ₁ -C ₆ alkyl, and R ₂₃ is unsubstituted C ₁ -C ₆ alkyl, There are compounds. In another embodiment are compounds of formula (VI), wherein m is 2. In another embodiment are compounds of formula (VI), wherein m is 3. In another embodiment, R ₆ is

There is a compound of formula (VI) In another embodiment, R ₆ is

There is a compound of formula (VI) In another embodiment are compounds of formula (VI), wherein R ₁₃ is H, or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, each R ₁ is independently halogen, —OCF ₃ , —CF ₃ , unsubstituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ alkoxy, ). In another embodiment are compounds of formula (VI), wherein each R ₁ is independently halogen. In another embodiment are compounds of formula (VI), wherein n is 1. In another embodiment are compounds of formula (VI), wherein each R ₁ is independently halogen. In another embodiment are compounds of formula (VI), wherein n is 2. In another embodiment are compounds of formula (VI), wherein each R ₁ is independently halogen. In another embodiment are compounds of formula (VI), wherein n is 0.

  In another aspect, the pharmaceutical composition comprises a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and at least one pharmaceutical agent Containing a commercially acceptable excipient. In another aspect, the pharmaceutical composition comprises a compound of formula (I), (II), (IIA), or (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and at least Contains one pharmaceutically acceptable excipient.

  In another aspect, a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, pharmacology, for the formulation of a drug to inhibit the activity of Olig2 in a cell Use of a pharmaceutically acceptable solvate or a pharmaceutically acceptable prodrug is provided. The method includes contacting a cell with a compound of formula (I), (II), or (IIA), including embodiments thereof.

  In another aspect, a compound of formula (I), (II), (IIA), or (VI), or a pharmaceutically acceptable salt thereof, for the formulation of a drug to inhibit the activity of Olig2 in a cell Use of possible salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable prodrugs is provided. The method includes contacting a cell with a compound of formula (I), (II), (IIA), or (VI), including embodiments thereof.

  In a further aspect, a subject in need thereof is a composition comprising a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. There are methods of treating a disease, disorder, or condition in a subject that would benefit from inhibition of Olig2 activity, comprising administering to the body. In some embodiments, a composition comprising a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is required. There is a method of treating a disease, disorder or condition in a subject that would benefit from inhibition of Olig2 activity, comprising administering to the subject subject, wherein the disease is cancer or Down's syndrome.

  In a further aspect, a composition comprising a compound of formula (I), (II), (IIA), or (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, There are methods of treating a disease, disorder, or condition in a subject that would benefit from inhibition of Olig2 activity, comprising administering to a subject in need. In some embodiments, a composition comprising a compound of formula (I), (II), (IIA), or (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof There is a method of treating a disease, disorder or condition in a subject that would benefit from inhibition of Olig2 activity, comprising administering to a subject in need thereof, wherein the disease is cancer or Down's syndrome.

  In another aspect, there is a need for a composition comprising a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. There is a method of treating a disease in a subject comprising administering to the subject, wherein the disease is cancer or Down's syndrome. In some embodiments, a composition comprising a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is required. There is a method of treating cancer in a subject comprising administering to the subject. In some embodiments, a composition comprising a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is required. There is a method of treating Down's syndrome in a subject comprising the step of administering to said subject.

  In another aspect, a composition comprising a compound of formula (I), (II), (IIA), or (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, There is a method of treating a disease in a subject comprising administering to a subject in need thereof, wherein the disease is cancer or Down's syndrome. In some embodiments, a composition comprising a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is required. There is a method of treating cancer in a subject comprising administering to the subject. In some embodiments, a composition comprising a compound of formula (I), (II), (IIA), or (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof There is a method of treating Down's syndrome in a subject comprising administering to a subject in need thereof.

  In another embodiment, a composition comprising a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is required There is a method of treating cancer in a subject comprising administering to a subject, wherein the cancer is brain cancer, glioblastoma multiforme, medulloblastoma, astrocytoma, brainstem glioma, Meningioma, oligodendroma, melanoma, lung cancer, breast cancer, or leukemia. In another embodiment, a composition comprising a compound of formula (I), (II), (IIA), or (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, There is a method of treating cancer in a subject comprising administering to a subject in need thereof, wherein the cancer is brain cancer, glioblastoma multiforme, medulloblastoma, astrocytoma, brain stem Glioma, meningioma, oligodendroglioma, melanoma, lung cancer, breast cancer, or leukemia.

  In another aspect, a method of inhibiting the activity of Olig2 in a cell comprising a compound of formula (I), (II), or (IIA), or a pharmaceutically acceptable salt, solvate thereof, Alternatively, there is a method comprising contacting a cell with a prodrug. In another aspect, a method of inhibiting the activity of Olig2 in a cell comprising a compound of formula (I), (II), (IIA), or (VI), or a pharmaceutically acceptable salt thereof, There are methods comprising contacting a cell with a solvate, or prodrug.

  In another aspect is the use of a compound of formula (I), (II), or (IIA) in the manufacture of a medicament for the treatment of a disease, disorder, or condition that would benefit from inhibition of Olig2 activity. In another aspect, the use of a compound of formula (I), (II), (IIA), or (VI) in the manufacture of a medicament for the treatment of a disease, disorder, or disease that would benefit from inhibition of Olig2 activity. is there.

  The function and advantage of other objects, compounds, compositions, methods, and also used herein will become apparent from the following detailed description. However, the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only and various changes and modifications within the spirit and scope of the disclosure will be apparent from this detailed description. Please understand that.

  The compounds described herein are modulators or inhibitors of neurogenic and GBM (Glioblastoma multiforme) stem cell transcriptional repressor OLIG2 (eg NM_005806, NP_005797 for humans). OLIG2 (also referred to herein as Olig2) is oligodendrocyte transcription factor 2. This protein is a member of the bHLH (basic helix loop helix) family. The bHLH family is a family of transcription factors that contain structural motifs characterized by two alpha helices connected by a loop. Transcription factors that include a bLHL domain are generally dimers. In general, one of the helices contains a basic amino acid residue that facilitates binding to DNA. OLIG2 is usually restricted to the central nervous system (CNS) in a non-disease state, where OLIG2 is an essential regulator of progenitor cell fate. OLIG2 binds to and suppresses the p21 gene promoter among other effects by homodimerization and heterodimerization with the E12 or E47 protein. P21 is a stem cell and tumor suppressor gene and is directly suppressed by OLIG2. P21 is activated by the tumor suppressor gene p53. p53 occurs in an intact wild-type form in approximately 70% of primary GBM patient samples. OLIG2 is highly expressed in all diffuse gliomas and is found in virtually 100% of GBM cells positive for the CD133 stem cell marker. Importantly, OLIG2 is generally not found in the normal brain and is not found in tissues outside the CNS unless it is malignant, such as T cell leukemia, melanoma, lung cancer, and breast cancer. None of the other nerve or glial marker genes or other transcriptional repressors show a consistent link to breast cancer. In contrast, membrane receptors (EGFR, PDGFR, etc.) do not express uniformly among patients, and various approaches to targeting membrane receptors have limited success with GBM treatment.

  Olig2 expression in diffuse gliomas results from the transformed stem cells of these tumors. It has been found that a small cohort of cells present in the patient's GBM expresses neural stem cell markers including CD133 and nestin, among others. CD133 (+) cells isolated from existing GBM are highly tumorigenic when transplanted orthotopically into mice. In one study, as few as 100 CD133 (+) cells extracted from a patient's GBM produced invasive tumors when transplanted into the brains of recipient mice, but 100,000 CD133 (− ) GBM cells were unable to generate tumors. Consistent with these findings, a significantly higher percentage of GBM occurs in close proximity to the neural stem cell embryonic area in the brain, ie, neural stem cells undergo malignant transformation and are at a certain distance from the embryonic area. Move and establish GBM.

  Another important finding for GBM cancer stem cells (CSCs) is that CD133 (+) cells are more sensitive to radiation and cytotoxic drugs used to treat GBM than masses composed of CD133 (-) cells. It has a very strong tolerance. This suggests that conventional radiation / chemotherapy leaves CSCs in the GBM, and if these cells are not targeted, the tumor will always be revived with a lethal effect. In addition, very few patients who survive GBM suffer from morbidity throughout their lives due to chemotoxicity and radiotoxicity in terms of cognition, endocrine balance, and other functions.

  Olig2 is highly expressed in GBM CSCs, but is only expressed at low levels in normal brain and is not detected in tissues outside the nervous system. Olig2 inhibitors will provide better therapeutic margin than conventional chemotherapy. Low systemic toxicity would be much more compatible with GBM's long-term clinical management than currently used treatment approaches.

  Brain cancer is a leading cause of cancer-related death in men, women, and children because of the high mortality rate of patients with brain cancer. Primary brain tumors are indeed the most common solid tumor in childhood and the second leading cause of cancer death following leukemia. The toxicity of modern treatments results in serious life-long morbidity in the few surviving patients. The development of small molecules, ie drugs that are effective against brain cancer, low toxicity and can be taken orally, represents an important advance. Furthermore, the compounds may be effective in other cancers driven by stem cells and highly expressing Olig2. Such cancers include T cell leukemia, skin cancer, small cell lung cancer, and breast cancer. In addition, these cancers often metastasize to the brain. This will involve millions of patients worldwide.

  In some embodiments described herein, glioblastoma and other brain cancers, ie, medulloblastoma, astrocytoma, brainstem glioma, meningioma, and oligodendroma There is a small molecule that inhibits Olig2, a transcription factor that is essential for the survival and growth of. Olig2 is detected mainly in the brain, generally not detected outside the nervous system, and is highly expressed in glioblastoma tumors. This means that inhibition of Olig2 is relatively low in toxicity to patients. Olig2 is overexpressed in melanoma, lung cancer, breast cancer, and T cell leukemia, and thus Olig2 inhibitors may be applicable to the treatment of such cancers.

  No other transcription factor or marker is as consistently associated with brain cancer as Olig2 and therefore inhibition of Olig2 should not be as good as other signal pathway inhibitors in glioblastoma It is. Olig2 is a robust target in that the hinge region of its dimerization loop is unique compared to other proteins of the class (basic helix-loop-helix proteins).

  It should be understood that the inhibitors described herein that target Olig2 are unique in terms of efficacy and toxicity.

  Existing drugs, therapies, and methods used to treat brain cancer include temozolomide (TMZ-Temodar), radiation, cyclophosphamide, carbastine, carboplatin, and occasional Avastin supplementation. These are all standard brain cancer drugs with negligible effects and are very toxic. There are currently no brain cancer stem cell inhibitors for brain tumors.

  In another aspect, a method of inhibiting the activity of OLIG2 is provided. The method comprises an effective amount of a compound described herein (eg, formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV ), (V), or (VI) compound) is contacted with Olig2 protein. The compound may have the structure of the formula provided herein (or any of its embodiments described above). In some embodiments, the method of inhibiting Olig2 protein is performed intracellularly. Accordingly, in certain embodiments, a method of inhibiting the activity of Olig2 in a cell is provided. The method includes contacting the cell with an effective amount of a compound provided herein. The compound may have the structure of the formula provided herein (or any of its embodiments described above). In some embodiments, the cell is prokaryotic or eukaryotic. The cell may be eukaryotic (eg, protozoan cell, fungal cell, plant cell, or animal cell). In some embodiments, the cell is a mammalian cell, such as a human cell, cow cell, pig cell, horse cell, dog and cat cell, mouse cell, or rat cell. In some embodiments, the cell is a mammalian cell. Cells may form part of an organ or organism. In certain embodiments, the cells do not form part of an organ or organism.

  In another aspect, a method of inhibiting the activity of Olig2 in a cell is provided. The method can include compounds provided herein (eg, formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), and ( V)) includes a step of contacting the cells. In some embodiments, the compound binds to the hinge region of the Olig2 dimerization loop. In some embodiments, the compound inhibits Olig2 dimerization.

Compounds The compounds described herein may be used in the treatment of diseases or conditions that inhibit the activity of Olig2 in cells and where inhibition of Olig2 activity has a beneficial effect.

  In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein,

Where
A is a single bond, O, or N (R ₁₀ );
X, Y, and Z are each independently N or C (R ₇ ), and at least one of X, Y, and Z is N;
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ ,-(C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), or

And
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
J is C (H) or N;
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
Each R ₇ is independently H, halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H, or unsubstituted C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-5,
p is 1-3;
q is 1-3.

In one embodiment are compounds of formula (I) wherein A is O or N (R ₁₀ ). In another embodiment are compounds of formula (I), wherein A is O or N (H). In another embodiment are compounds of formula (I) wherein A is O. In another embodiment are compounds of formula (I), wherein A is N (R ₁₀ ). In another embodiment are compounds of formula (I), wherein A is N (H). In another embodiment are compounds of formula (I), wherein A is N (CH ₃ ). In another embodiment are compounds of formula (I), wherein A is a single bond.

In another embodiment are compounds of formula (I), wherein R ₆ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (I), wherein R ₆ is substituted or unsubstituted cyclopropyl. In another embodiment are compounds of formula (I), wherein R ₆ is substituted or unsubstituted cyclobutyl. In another embodiment are compounds of formula (I), wherein R ₆ is substituted or unsubstituted cyclopentyl. In another embodiment are compounds of formula (I), wherein R ₆ is substituted or unsubstituted cyclohexyl.

In another embodiment are compounds of formula (I), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, R ₆ is substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl, benzothiol Phenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxiadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl, purinyl, furopyridinyl, thienopyridinyl, fluoropyrrolyl, Furofuranyl, thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl, thienothiophenyl, quino There are compounds of formula (I) which are linyl, isoquinolinyl, quinoxalinyl, furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, and benzoisoxazolyl. In another embodiment are compounds of formula (I), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment are compounds of formula (I), wherein R ₆ is substituted pyridyl. In another embodiment are compounds of formula (I), wherein R ₆ is unsubstituted pyridyl.

In another embodiment are compounds of formula (I), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment are compounds of formula (I), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , and R ₁₄ and R ₁₅ are each H. In another embodiment, the compounds of formula (I), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 2, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, the compound of formula (I), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —OH.

In another embodiment, the compounds of formula (I), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 3, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, a compound of formula (I) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —OH.

In another embodiment are compounds of formula (I), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₄ and R ₁₅ are each H. There are compounds of formula (I). In another embodiment, the compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (I) wherein R ₁₂ is H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is H. There are compounds of I). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (I), wherein R ₁₂ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is CH _3. There are compounds of (I). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (I) which forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There are compounds of formula (I) that form. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There are compounds of formula (I) that form.

In another embodiment are compounds of formula (I), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₄ and R ₁₅ are each H. There are compounds of formula (I). In another embodiment, the compounds of formula (I), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (I) wherein R ₁₂ is H. In another embodiment, the formula ( ₆ ) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ , and R ₁₂ is H. There are compounds of I). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (I), wherein R ₁₂ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, the formula wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ and R ₁₂ is CH _3. There are compounds of (I). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (I) which forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There are compounds of formula (I) that form. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There are compounds of formula (I) that form.

In another embodiment are compounds of formula (I), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, R ₆ is

There are compounds of formula (I) In another embodiment, R ₆ is

There is a compound of formula (I) wherein J is C (H). In another embodiment, R ₆ is

There are compounds of formula (I), wherein J is C (H), p is 1 and q is 1. In another embodiment, R ₆ is

There are compounds of formula (I) wherein J is C (H), p is 2 and q is 1. In another embodiment, R ₆ is

And a compound of formula (I) wherein J is C (H), p is 3 and q is 1. In another embodiment, R ₆ is

Are compounds of formula (I) wherein J is C (H), p is 2 and q is 2. In another embodiment, R ₆ is

There are compounds of formula (I), wherein J is C (H), p is 1, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There are compounds of formula (I), wherein J is C (H), p is 2, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There are compounds of formula (I), wherein J is C (H), p is 3, q is 1 and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There are compounds of formula (I), wherein J is C (H), p is 2, q is 2, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment, R ₆ is

There are compounds of formula (I) wherein J is N. In another embodiment, R ₆ is

There is a compound of formula (I) wherein J is N, p is 2 and q is 2. In another embodiment, R ₆ is

There are compounds of formula (I), wherein J is N, p is 2, q is 2, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment are compounds of formula (I), wherein R ₅ is halogen. In another embodiment are compounds of formula (I), wherein R ₅ is —CF ₃ . In another embodiment are compounds of formula (I), wherein R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (I), wherein R ₅ is —CH ₃ . In another embodiment are compounds of formula (I), wherein R ₅ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (I), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl. In another embodiment are compounds of formula (I), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment are compounds of formula (I), wherein R ₅ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (I), wherein R ₅ is substituted or unsubstituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (I), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There are compounds of (I). In another embodiment are compounds of formula (I) wherein R ₂ and R ₃ are each H.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, and , Wherein at least one of R ₂ and R ₃ is not H. In another embodiment are compounds of formula (I), wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (I), wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (I), wherein R ₂ is H and R ₃ is C ₃ -C ₆ cycloalkyl. In another embodiment are compounds of formula (I) wherein R ₂ is H and R ₃ is cyclopropyl. In another embodiment are compounds of formula (I) wherein R ₂ is H and R ₃ is cyclopentyl. In another embodiment are compounds of formula (I) wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (I) wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (I) wherein R ₂ is CH ₃ and R ₃ is H. In another embodiment are compounds of formula (I), wherein R ₂ is C ₃ -C ₆ cycloalkyl and R ₃ is H. In another embodiment are compounds of formula (I) wherein R ₂ is cyclopropyl and R ₃ is H. In another embodiment are compounds of formula (I) wherein R ₂ is cyclopentyl and R ₃ is H.

In another embodiment are compounds of formula (I), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (I), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment are compounds of formula (I), wherein R ₂ and R ₃ are joined to form a 6-membered heterocycle.

  In another embodiment are compounds of formula (I), wherein n is 0.

In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N. _{(R 8) S (= O} ) 2 R 9, S (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O ) R ₉ , —CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} A C ₇ heteroaryl are the compounds of formula (I). In another embodiment, each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. There are compounds of formula (I) In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted Or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl , substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl are the compounds of formula (I). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (I) which are substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (I), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (I), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 2. In another embodiment are compounds of formula (I) wherein n is 3 and each R ₁ is independently halogen. In another embodiment are compounds of formula (I) wherein n is 2 and each R ₁ is independently halogen. In another embodiment are compounds of formula (I), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment are compounds of formula (I) wherein n is 2 and R ₁ is each F. In another embodiment are compounds of formula (I) wherein n is 2 and each R ₁ is independently Cl. In another embodiment are compounds of formula (I) wherein n is 2 and each R ₁ is independently halogen or —CF ₃ . In another embodiment are compounds of formula (I), wherein n is 2 and each R ₁ is independently F or —CF ₃ . In another embodiment are compounds of formula (I), wherein n is 2 and each R ₁ is independently Cl or —CF ₃ . In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is halogen. In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is F. In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is Cl. In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is —CF ₃ . In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is CH ₃ . In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is —OCH ₃ . In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is —OCF ₃ . In another embodiment are compounds of formula (I) wherein n is 1 and R ₁ is —OCF ₂ H.

In a further embodiment of the foregoing embodiments of formula (I), X is C (R ₇ ), Y is N, and Z is N. In a further embodiment of the foregoing embodiments of formula (I), X is C (H), Y is N, and Z is N. In a further embodiment of the foregoing embodiments of formula (I), X is C (R ₇ ), Y is C (R ₇ ), and Z is N. In a further embodiment of the foregoing embodiments of formula (I), X is C (H), Y is C (H), and Z is N. In a further embodiment of the foregoing embodiments of formula (I), X is C (R ₇ ), Y is N, and Z is C (R ₇ ). In a further embodiment of the foregoing embodiments of formula (I), X is C (H), Y is N, and Z is C (H). In a further embodiment of the foregoing embodiments of formula (I), X is C (R ₇ ), Y is C (R ₇ ), and Z is C (R ₇ ). In a further embodiment of the foregoing embodiments of formula (I), X is C (H), Y is C (H), and Z is C (H).

  In another aspect, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein,

Where
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , or

And
J is C (H),
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C, ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H, or unsubstituted C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-5,
p is 1-3;
q is 1-3.

In another embodiment are compounds of formula (II), wherein R ₆ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (II), wherein R ₆ is substituted or unsubstituted cyclopropyl. In another embodiment are compounds of formula (II), wherein R ₆ is substituted or unsubstituted cyclobutyl. In another embodiment are compounds of formula (II), wherein R ₆ is substituted or unsubstituted cyclopentyl. In another embodiment are compounds of formula (II), wherein R ₆ is substituted or unsubstituted cyclohexyl.

In another embodiment are compounds of formula (II), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, R ₆ is substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl, benzothiol Phenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxiadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl, purinyl, furopyridinyl, thienopyridinyl, fluoropyrrolyl, Furofuranyl, thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl, thienothiophenyl, quino There are compounds of formula (II) which are linyl, isoquinolinyl, quinoxalinyl, furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, and benzisoxazolyl. In another embodiment are compounds of formula (II), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment are compounds of formula (II), wherein R ₆ is substituted pyridyl. In another embodiment are compounds of formula (II), wherein R ₆ is unsubstituted pyridyl.

In another embodiment are compounds of formula (II), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment are compounds of formula (II), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , and R ₁₄ and R ₁₅ are each H. In another embodiment, the compounds of formula (II), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 2, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment are compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is substituted phenyl. In another embodiment, the compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —OH. In another embodiment, Formula (II) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —N (R ₂₂ ) S (═O) ₂ R _23. There are compounds. In another embodiment, R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —N (R ₂₂ ) C (═O) R ₂₃ There are compounds. In another embodiment, a compound of formula (II) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₁ -C ₆ alkoxy. is there. In another embodiment of the foregoing embodiments, each R ₂₂ is independently H, or unsubstituted C ₁ -C ₆ alkyl, and R ₂₃ is unsubstituted C ₁ -C ₆ alkyl. There is a compound of formula (II).

In another embodiment, the compounds of formula (II), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 3, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment are compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is substituted phenyl. In another embodiment, the compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (II), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —OH. In another embodiment, Formula (II) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —N (R ₂₂ ) S (═O) ₂ R _23. There is a compound. In another embodiment, R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —N (R ₂₂ ) C (═O) R ₂₃ There are compounds. In another embodiment, a compound of formula (II) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₁ -C ₆ alkoxy. is there. In another embodiment of the foregoing embodiments, each R ₂₂ is independently H, or unsubstituted C ₁ -C ₆ alkyl, and R ₂₃ is unsubstituted C ₁ -C ₆ alkyl. There is a compound of formula (II).

In another embodiment are compounds of formula (II), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, R ₆ is

And a compound of formula (II) wherein J is C (H). In another embodiment, R ₆ is

And a compound of formula (II) wherein J is C (H), p is 1 and q is 1. In another embodiment, R ₆ is

And a compound of formula (II) wherein J is C (H), p is 2 and q is 1. In another embodiment, R ₆ is

And a compound of formula (II) wherein J is C (H), p is 3 and q is 1. In another embodiment, R ₆ is

And a compound of formula (II) wherein J is C (H), p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (II), wherein J is C (H), p is 1, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (II), wherein J is C (H), p is 2, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (II), wherein J is C (H), p is 3, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (II), wherein J is C (H), p is 2, q is 2, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment are compounds of formula (II), wherein R ₅ is halogen. In another embodiment are compounds of formula (II), wherein R ₅ is —CF ₃ . In another embodiment are compounds of formula (II), wherein R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (II), wherein R ₅ is —CH ₃ . In another embodiment are compounds of formula (II) wherein R ₅ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (II), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl. In another embodiment are compounds of formula (II), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment are compounds of formula (II), wherein R ₅ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (II), wherein R ₅ is substituted or unsubstituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (II), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There is a compound of (II). In another embodiment are compounds of formula (II), wherein R ₂ and R ₃ are each H.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, and , Wherein at least one of R ₂ and R ₃ is not H. In another embodiment are compounds of formula (II) wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (II) wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (II), wherein R ₂ is H and R ₃ is C ₃ -C ₆ cycloalkyl. In another embodiment are compounds of formula (II) wherein R ₂ is H and R ₃ is cyclopropyl. In another embodiment are compounds of formula (II), wherein R ₂ is H and R ₃ is cyclopentyl. In another embodiment are compounds of formula (II) wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (II), wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (II) wherein R ₂ is CH ₃ and R ₃ is H. In another embodiment are compounds of formula (II), wherein R ₂ is C ₃ -C ₆ cycloalkyl and R ₃ is H. In another embodiment are compounds of formula (II) wherein R ₂ is cyclopropyl and R ₃ is H. In another embodiment are compounds of formula (II) wherein R ₂ is cyclopentyl and R ₃ is H.

In another embodiment are compounds of formula (II), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (II), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment are compounds of formula (II), wherein R ₂ and R ₃ are joined to form a 6 membered heterocycle.

  In another embodiment are compounds of formula (II), wherein n is 0.

In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ). _{S (= O) 2 R 9} , S (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, _{-CO 2 R 8, -N (R} 8) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C _3- C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ het, Aryl are the compounds of formula (II). In another embodiment, each R ₁ is independently halogen, —CN, —OH, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy, There is a compound of (II). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted. C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted There are compounds of formula (II) which are substituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted. it is a _C 1 -C ₆ alkoxy, a compound of formula (II). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted. There are compounds of formula (II), wherein C ₁ -C ₆ alkoxy is n and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted. There are compounds of formula (II), wherein C ₁ -C ₆ alkoxy is n and n is 2. In another embodiment are compounds of formula (II), wherein n is 3 and each R ₁ is independently halogen. In another embodiment are compounds of formula (II) wherein n is 2 and each R ₁ is independently halogen. In another embodiment are compounds of formula (II), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment are compounds of formula (II) wherein n is 2 and each R ₁ is F. In another embodiment are compounds of formula (II) wherein n is 2 and each R ₁ is independently Cl. In another embodiment are compounds of formula (II) wherein n is 1 and R ₁ is halogen. In another embodiment are compounds of formula (II) wherein n is 1 and R ₁ is F. In another embodiment are compounds of formula (II), wherein n is 1 and R ₁ is Cl. In another embodiment are compounds of formula (II) wherein n is 1 and R ₁ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (II) wherein n is 1 and R ₁ is CH ₃ . In another embodiment are compounds of formula (II) wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment are compounds of formula (II) wherein n is 1 and R ₁ is —OCH ₃ . In another embodiment are compounds of formula (II) wherein n is 1 and R ₁ is —OCF ₃ . In another embodiment are compounds of formula (II) wherein n is 1 and R ₁ is —OCF ₂ H.

  In another embodiment, a compound of formula (IIA), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein,

Where
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (═O) _2. R ₉ , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO ₂ R ₈ , _{-N (R 8) 2, -C} (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted Substituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, Or, two R ₁ s together, form a substituted or unsubstituted heterocyclic or substituted or unsubstituted ring carbon,
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₄ is H, halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (═O) ₂ R _9. , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl substituted, or a substituted or unsubstituted _C 2 -C ₇ heteroaryl, or 2 The of R ₁ together, a substituted or unsubstituted heterocyclic ring, or form a substituted or unsubstituted carbocyclic ring, wherein, when n is 0, R ₄ is not a halogen,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ),
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H or C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-4.

In one embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), and R ₁₄ and R ₁₅ are each H; There are compounds. In another embodiment are compounds of formula (IIA), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), and R ₁₁ and R ₁₂ are each H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, and R ₁₂ is H. There is a compound of formula (IIA). In another embodiment are compounds of formula (IIA), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), R ₁₁ is CH ₃ , and R ₁₂ is H. . In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, and R ₁₂ is substituted or unsubstituted. _C 1 -C ₆ alkyl substituted are the compounds of formula (IIA). In another embodiment, a compound of formula (IIA) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), R ₁₁ is CH ₃ , and R ₁₂ is CH ₃ is there. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), and R ₁₁ and R ₁₂ together form a 5, 6, 7, or 8 membered heterocyclic ring. There are compounds of formula (IIA) that form In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), and R ₁₁ and R ₁₂ together form a 5-membered heterocycle, (IIA ). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), and R ₁₁ and R ₁₂ together form a 6-membered heterocyclic ring, ).

In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (IIA). In another embodiment, the compounds of formula (IIA) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IIA), wherein R ₁₂ is H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is H. IIA). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IIA), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is CH _3. There is a compound of (IIA). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (IIA) which forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There is a compound of formula (IIA) that forms. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There is a compound of formula (IIA) that forms.

In another embodiment are compounds of formula (IIA), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (IIA). In another embodiment, the compounds of formula (IIA) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (IIA), wherein R ₁₂ is H. In another embodiment, the formula ( ₆ ) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ , and R ₁₂ is H. IIA). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (IIA), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, the formula wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ and R ₁₂ is CH _3. There is a compound of (IIA). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (IIA) which forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There is a compound of formula (IIA) that forms. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There is a compound of formula (IIA) that forms.

In another embodiment are compounds of formula (IIA), wherein R ₅ is halogen. In another embodiment are compounds of formula (IIA), wherein R ₅ is —CF ₃ . In another embodiment are compounds of formula (IIA), wherein R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (IIA), wherein R ₅ is —CH ₃ . In another embodiment are compounds of formula (IIA), wherein R ₅ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (IIA), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl. In another embodiment are compounds of formula (IIA), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment are compounds of formula (IIA), wherein R ₅ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (IIA), wherein R ₅ is substituted or unsubstituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (IIA), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There is a compound of (IIA). In another embodiment are compounds of formula (IIA), wherein R ₂ and R ₃ are each H.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, and There is a compound of formula (IIA) wherein at least one of R ₂ and R ₃ is not H. In another embodiment are compounds of formula (IIA), wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (IIA), wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (IIA), wherein R ₂ is H and R ₃ is C ₃ -C ₆ cycloalkyl. In another embodiment are compounds of formula (IIA), wherein R ₂ is H and R ₃ is cyclopropyl. In another embodiment are compounds of formula (IIA), wherein R ₂ is H and R ₃ is cyclopentyl. In another embodiment are compounds of formula (IIA), wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (IIA), wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (IIA), wherein R ₂ is CH ₃ and R ₃ is H. In another embodiment are compounds of formula (IIA), wherein R ₂ is C ₃ -C ₆ cycloalkyl and R ₃ is H. In another embodiment are compounds of formula (IIA) wherein R ₂ is cyclopropyl and R ₃ is H. In another embodiment are compounds of formula (IIA), wherein R ₂ is cyclopentyl and R ₃ is H.

In another embodiment are compounds of formula (IIA), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (IIA), wherein R ₂ and R ₃ are joined to form a 5-membered heterocycle. In another embodiment are compounds of formula (IIA), wherein R ₂ and R ₃ are taken together to form a 6-membered heterocycle.

  In another embodiment are compounds of formula (IIA), wherein n is 0.

In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ). _{S (= O) 2 R 9} , S (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, _{-CO 2 R 8, -N (R} 8) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C _3- C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ het, Aryl are the compounds of formula (IIA). In another embodiment, each R ₁ is independently halogen, —CN, —OH, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy, There is a compound of (IIA). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted. C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted There are compounds of formula (IIA) which are substituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted. There are compounds of formula (IIA) which are C ₁ -C ₆ alkoxy. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted. There are compounds of formula (IIA), wherein C ₁ -C ₆ alkoxy is n and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted. There are compounds of formula (IIA), wherein C ₁ -C ₆ alkoxy is n and n is 2. In another embodiment are compounds of formula (IIA), wherein n is 3 and each R ₁ is independently halogen. In another embodiment are compounds of formula (IIA), wherein n is 2 and each R ₁ is independently halogen. In another embodiment are compounds of formula (IIA), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment are compounds of formula (IIA) wherein n is 2 and each R ₁ is F. In another embodiment are compounds of formula (IIA) wherein n is 2 and each R ₁ is independently Cl. In another embodiment are compounds of formula (IIA) wherein n is 1 and R ₁ is halogen. In another embodiment are compounds of formula (IIA) wherein n is 1 and R ₁ is F. In another embodiment are compounds of formula (IIA) wherein n is 1 and R ₁ is Cl. In another embodiment are compounds of formula (IIA) wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (IIA) wherein n is 1 and R ₁ is CH ₃ . In another embodiment are compounds of formula (IIA), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment are compounds of formula (IIA), wherein n is 1 and R ₁ is —OCH ₃ . In another embodiment are compounds of formula (IIA), wherein n is 1 and R ₁ is —OCF ₃ . In another embodiment are compounds of formula (IIA), wherein n is 1 and R ₁ is —OCF ₂ H.

In another embodiment, R ₄ is H, halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (= O) ₂ R ₉ , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO _{2 R 8, -N (R 8)} 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, Alternatively there are compounds of formula (IIA) which are substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment, R ₄ is H, halogen, —CN, —OH, —OCF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy, There are compounds of formula (IIA). In another embodiment are compounds of formula (IIA) wherein R ₄ is H. In another embodiment are compounds of formula (IIA), wherein R ₄ is halogen. In another embodiment are compounds of formula (IIA), wherein R ₄ is F. In another embodiment are compounds of formula (IIA), wherein R ₄ is Cl. In another embodiment are compounds of formula (IIA), wherein R ₄ is Br. In another embodiment are compounds of formula (IIA), wherein R ₄ is —CF ₃ . In another embodiment are compounds of formula (IIA), wherein R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IIA), wherein R ₄ is —CH ₃ . In another embodiment are compounds of formula (IIA), wherein R ₄ is —OCH ₃ .

In another embodiment are compounds of formula (IIA) wherein n is 0 and R ₄ is H. In another embodiment are compounds of formula (IIA) wherein n is 0 and R ₄ is halogen. In another embodiment are compounds of formula (IIA) wherein n is 0 and R ₄ is F. In another embodiment are compounds of formula (IIA), wherein n is 0 and R ₄ is Cl. In another embodiment are compounds of formula (IIA), wherein n is 0 and R ₄ is Br. In another embodiment are compounds of formula (IIA), wherein n is 0 and R ₄ is —CF ₃ . In another embodiment are compounds of formula (IIA), wherein n is 0 and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IIA), wherein n is 0 and R ₄ is —CH ₃ . In another embodiment are compounds of formula (IIA), wherein n is 0 and R ₄ is —OCH ₃ .

In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is Cl, and R ₄ is Cl. In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —CH ₃ and R ₄ is Cl. In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —OCH ₃ and R ₄ is Cl. In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —CF ₃ and R ₄ is Cl. In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is —OCF ₃ , and R ₄ is Cl. In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is Cl, and R ₄ is F. In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —CH ₃ and R ₄ is F. In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —OCH ₃ and R ₄ is F. In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is —CF ₃ , and R ₄ is F. In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is —OCF ₃ , and R ₄ is F. In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is Cl and R ₄ is H. In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —CH ₃ , and R ₄ is H. In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —OCH ₃ and R ₄ is H. In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is —CF ₃ , and R ₄ is H. In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —OCF ₃ and R ₄ is H. In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is Cl, and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —CH ₃ and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —OCH ₃ and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —CF ₃ and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —OCF ₃ and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is Cl, and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —CH ₃ and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is —OCH ₃ , and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IIA) wherein n is 1, R ₁ is —CF ₃ , and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IIA), wherein n is 1, R ₁ is —OCF ₃ , and R ₄ is —OCF ₃ .

  In another embodiment, described herein is a compound of formula (IIA '), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

Where
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (═O) _2. R ₉ , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO ₂ R ₈ , _{-N (R 8) 2, -C} (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted Substituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, Or, two R ₁ s together, form a substituted or unsubstituted heterocyclic or substituted or unsubstituted ring carbon,
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₄ is H, F, Cl, Br, I, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, Oh There are two R ₁ together form a substituted or unsubstituted heterocyclic or substituted or unsubstituted carbocyclic ring, wherein, when n is 0, R ₄ is instead Cl,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ),
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H or C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-4.

  In another embodiment, a compound of formula (IIB), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as described herein,

Where
A is O,
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ ,-(C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), or

And
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
J is C (H),
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ Alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C _6- be a C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
m is 2-6,
n is 0-5,
p is 1-3;
q is 1-3.

In another embodiment are compounds of formula (IIB), wherein R ₆ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (IIB), wherein R ₆ is substituted or unsubstituted cyclopropyl. In another embodiment are compounds of formula (IIB), wherein R ₆ is substituted or unsubstituted cyclobutyl. In another embodiment are compounds of formula (IIB), wherein R ₆ is substituted or unsubstituted cyclopentyl. In another embodiment are compounds of formula (IIB), wherein R ₆ is substituted or unsubstituted cyclohexyl.

In another embodiment are compounds of formula (IIB), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, R ₆ is substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl, benzothiol Phenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxiadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl, purinyl, furopyridinyl, thienopyridinyl, fluoropyrrolyl, Furofuranyl, thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl, thienothiophenyl, quino There are compounds of formula (IIB) which are linyl, isoquinolinyl, quinoxalinyl, furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, and benzisoxazolyl. In another embodiment are compounds of formula (IIB), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment are compounds of formula (IIB), wherein R ₆ is substituted pyridyl. In another embodiment are compounds of formula (IIB), wherein R ₆ is unsubstituted pyridyl.

In another embodiment are compounds of formula (IIB), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment are compounds of formula (IIB), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , and R ₁₄ and R ₁₅ are each H. In another embodiment, the compounds of formula (IIB), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 2, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, of Formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, a compound of formula (IIB) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —OH.

In another embodiment, the compounds of formula (IIB), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 3, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, of Formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, a compound of formula (IIB) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (IIB), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —OH.

In another embodiment are compounds of formula (IIB), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (IIB). In another embodiment, the compounds of formula (IIB), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IIB), wherein R ₁₂ is H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is H. IIB). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IIB), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is CH _3. There is a compound of (IIB). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (IIB) which forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There is a compound of formula (IIB) that forms. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There is a compound of formula (IIB) that forms.

In another embodiment are compounds of formula (IIB), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (IIB). In another embodiment, the compounds of formula (IIB) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (IIB), wherein R ₁₂ is H. In another embodiment, the formula ( ₆ ) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ , and R ₁₂ is H. IIB). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (IIB), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, the formula wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ and R ₁₂ is CH _3. There is a compound of (IIB). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (IIB) which forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There is a compound of formula (IIB) that forms. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There is a compound of formula (IIB) that forms.

In another embodiment are compounds of formula (IIB), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, R ₆ is

There is a compound of formula (IIB) wherein J is C (H). In another embodiment, R ₆ is

And a compound of formula (IIB) wherein J is C (H), p is 1 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (IIB), wherein J is C (H), p is 2 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (IIB), wherein J is C (H), p is 3 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (IIB), wherein J is C (H), p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (IIB), wherein J is C (H), p is 1, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (IIB), wherein J is C (H), p is 2, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (IIB), wherein J is C (H), p is 3, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (IIB), wherein J is C (H), p is 2, q is 2, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment are compounds of formula (IIB), wherein R ₅ is halogen. In another embodiment are compounds of formula (IIB), wherein R ₅ is —CF ₃ . In another embodiment are compounds of formula (IIB), wherein R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (IIB), wherein R ₅ is —CH ₃ . In another embodiment are compounds of formula (IIB), wherein R ₅ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (IIB), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl. In another embodiment are compounds of formula (IIB), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment are compounds of formula (IIB), wherein R ₅ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (IIB), wherein R ₅ is substituted or unsubstituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (IIB), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There is a compound of (IIB). In another embodiment are compounds of formula (IIB), wherein R ₂ and R ₃ are each H.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, and There is a compound of formula (IIB) wherein at least one of R ₂ and R ₃ is not H. In another embodiment are compounds of formula (IIB), wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (IIB) wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (IIB), wherein R ₂ is H and R ₃ is C ₃ -C ₆ cycloalkyl. In another embodiment are compounds of formula (IIB), wherein R ₂ is H and R ₃ is cyclopropyl. In another embodiment are compounds of formula (IIB), wherein R ₂ is H and R ₃ is cyclopentyl. In another embodiment are compounds of formula (IIB), wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (IIB), wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (IIB), wherein R ₂ is CH ₃ and R ₃ is H. In another embodiment are compounds of formula (IIB), wherein R ₂ is C ₃ -C ₆ cycloalkyl and R ₃ is H. In another embodiment are compounds of formula (IIB), wherein R ₂ is cyclopropyl and R ₃ is H. In another embodiment are compounds of formula (IIB), wherein R ₂ is cyclopentyl and R ₃ is H.

In another embodiment are compounds of formula (IIB), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (IIB), wherein R ₂ and R ₃ are joined to form a 5-membered heterocycle. In another embodiment are compounds of formula (IIB), wherein R ₂ and R ₃ are joined to form a 6-membered heterocycle.

In another embodiment are compounds of formula (IIB), wherein n is 0.
In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N. _{(R 8) S (= O} ) 2 R 9, S (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O ) R ₉ , —CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} A C ₇ heteroaryl are the compounds of formula (I). In another embodiment, each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. There is a compound of formula (IIB). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted Or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl Or a substituted or unsubstituted C ₆ -C ₁₀ aryl, or a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IIB) which are substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IIB), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IIB), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 2. In another embodiment are compounds of formula (IIB) wherein n is 3 and each R ₁ is independently halogen. In another embodiment are compounds of formula (IIB) wherein n is 2 and each R ₁ is independently halogen. In another embodiment are compounds of formula (IIB), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment are compounds of formula (IIB) wherein n is 2 and each R ₁ is F. In another embodiment are compounds of formula (IIB) wherein n is 2 and each R ₁ is independently Cl. In another embodiment are compounds of formula (IIB), wherein n is 2 and each R ₁ is independently halogen or —CF ₃ . In another embodiment are compounds of formula (IIB), wherein n is 2 and each R ₁ is independently F or —CF ₃ . In another embodiment are compounds of formula (IIB), wherein n is 2 and each R ₁ is independently Cl or —CF ₃ . In another embodiment are compounds of formula (IIB) wherein n is 1 and R ₁ is halogen. In another embodiment are compounds of formula (IIB) wherein n is 1 and R ₁ is F. In another embodiment are compounds of formula (IIB) wherein n is 1 and R ₁ is Cl. In another embodiment are compounds of formula (IIB) wherein n is 1 and R ₁ is —CF ₃ . In another embodiment are compounds of formula (IIB) wherein n is 1 and R ₁ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (IIB) wherein n is 1 and R ₁ is CH ₃ . In another embodiment are compounds of formula (IIB), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment are compounds of formula (IIB) wherein n is 1 and R ₁ is —OCH ₃ . In another embodiment are compounds of formula (IIB) wherein n is 1 and R ₁ is —OCF ₃ . In another embodiment are compounds of formula (IIB) wherein n is 1 and R ₁ is —OCF ₂ H.

  In another embodiment, a compound of formula (IIC), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein;

Where
A is a single bond,
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl,-(C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ ,-(C (R _{14) (R 15)) m} N (R 11) (R 12), or,

And
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
J is C (H),
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ Alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C _6- be a C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
m is 2-6,
n is 0-5,
p is 1-3;
q is 1-3.

In another embodiment are compounds of formula (IIC), wherein R ₆ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (IIC), wherein R ₆ is substituted or unsubstituted cyclopropyl. In another embodiment are compounds of formula (IIC), wherein R ₆ is substituted or unsubstituted cyclobutyl. In another embodiment are compounds of formula (IIC), wherein R ₆ is substituted or unsubstituted cyclopentyl. In another embodiment are compounds of formula (IIC), wherein R ₆ is substituted or unsubstituted cyclohexyl.

In another embodiment are compounds of formula (IIC), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, R ₆ is substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl, benzothiol Phenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxiadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl, purinyl, furopyridinyl, thienopyridinyl, fluoropyrrolyl, Furofuranyl, thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl, thienothiophenyl, quino There are compounds of formula (IIC) which are linyl, isoquinolinyl, quinoxalinyl, furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, and benzisoxazolyl. In another embodiment are compounds of formula (IIC), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment are compounds of formula (IIC), wherein R ₆ is substituted pyridyl. In another embodiment are compounds of formula (IIC), wherein R ₆ is unsubstituted pyridyl.

In another embodiment are compounds of formula (IIC), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment are compounds of formula (IIC), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , and R ₁₄ and R ₁₅ are each H. In another embodiment, the compounds of formula (IIC), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 2, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, of Formula (IIC), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (IIC), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, a compound of formula (IIC) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (IIC), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (IIC), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (IIC), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —OH.

In another embodiment, the compounds of formula (IIC) wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 3, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, of Formula (IIC): wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (IIC), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, a compound of formula (IIC) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (IIC), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (IIC), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (IIC), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —OH.

In another embodiment are compounds of formula (IIC), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (IIC). In another embodiment, the compounds of formula (IIC) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IIC), wherein R ₁₂ is H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is H. IIC). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IIC), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is CH _3. There is a compound of (IIC). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (IIC) which forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There is a compound of formula (IIC) that forms. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There is a compound of formula (IIC) that forms.

In another embodiment are compounds of formula (IIC), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (IIC). In another embodiment, the compounds of formula (IIC) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (IIC), wherein R ₁₂ is H. In another embodiment, the formula ( ₆ ) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ , and R ₁₂ is H. IIC). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (IIC), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, the formula wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ and R ₁₂ is CH _3. There is a compound of (IIC). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (IIC) which forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There is a compound of formula (IIC) that forms. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There is a compound of formula (IIC) that forms.

In another embodiment, R ₆ is

And a compound of formula (IIC) wherein J is C (H). In another embodiment, R ₆ is

There is a compound of formula (IIC) wherein J is C (H), p is 1 and q is 1. In another embodiment, R ₆ is

And a compound of formula (IIC) wherein J is C (H), p is 2 and q is 1.
In another embodiment, R ₆ is

And a compound of formula (IIC) wherein J is C (H), p is 3 and q is 1. In another embodiment, R ₆ is

And a compound of formula (IIC) wherein J is C (H), p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (IIC), wherein J is C (H), p is 1, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (IIC), wherein J is C (H), p is 2, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (IIC), wherein J is C (H), p is 3, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (IIC), wherein J is C (H), p is 2, q is 2, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment are compounds of formula (IIC), wherein R ₅ is halogen. In another embodiment are compounds of formula (IIC), wherein R ₅ is —CF ₃ . In another embodiment are compounds of formula (IIC), wherein R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (IIC), wherein R ₅ is —CH ₃ . In another embodiment are compounds of formula (IIC), wherein R ₅ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (IIC), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl. In another embodiment are compounds of formula (IIC), wherein R ₅ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment are compounds of formula (IIC), wherein R ₅ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (IIC), wherein R ₅ is substituted or unsubstituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (IIC), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There is a compound of (IIC). In another embodiment are compounds of formula (IIC), wherein R ₂ and R ₃ are each H.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, and There is a compound of formula (IIC) wherein at least one of R ₂ and R ₃ is not H. In another embodiment are compounds of formula (IIC), wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (IIC), wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (IIC), wherein R ₂ is H and R ₃ is C ₃ -C ₆ cycloalkyl. In another embodiment are compounds of formula (IIC), wherein R ₂ is H and R ₃ is cyclopropyl. In another embodiment are compounds of formula (IIC), wherein R ₂ is H and R ₃ is cyclopentyl. In another embodiment are compounds of formula (IIC), wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (IIC), wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (IIC), wherein R ₂ is CH ₃ and R ₃ is H. In another embodiment are compounds of formula (IIC), wherein R ₂ is C ₃ -C ₆ cycloalkyl and R ₃ is H. In another embodiment are compounds of formula (IIC), wherein R ₂ is cyclopropyl and R ₃ is H. In another embodiment are compounds of formula (IIC), wherein R ₂ is cyclopentyl and R ₃ is H.

In another embodiment are compounds of formula (IIC), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (IIC), wherein R ₂ and R ₃ are joined to form a 5-membered heterocycle. In another embodiment are compounds of formula (IIC), wherein R ₂ and R ₃ are taken together to form a 6-membered heterocycle.

  In another embodiment are compounds of formula (IIC), wherein n is 0.

In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N. _{(R 8) S (= O} ) 2 R 9, S (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O ) R ₉ , —CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} A C ₇ heteroaryl are the compounds of formula (IIC). In another embodiment, each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. There is a compound of formula (IIC) In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted Or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl Or a substituted or unsubstituted C ₆ -C ₁₀ aryl, or a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or a substituted or unsubstituted _C 1 -C ₆ alkoxy, a compound of formula (IIC). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IIC), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IIC), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 2. In another embodiment are compounds of formula (IIC) wherein n is 3 and each R ₁ is independently halogen. In another embodiment are compounds of formula (IIC) wherein n is 2 and each R ₁ is independently halogen. In another embodiment are compounds of formula (IIC), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment are compounds of formula (IIC) wherein n is 2 and each R ₁ is F. In another embodiment are compounds of formula (IIC), wherein n is 2 and each R ₁ is independently Cl. In another embodiment are compounds of formula (IIC) wherein n is 2 and each R ₁ is independently halogen or —CF ₃ . In another embodiment are compounds of formula (IIC), wherein n is 2 and each R ₁ is independently F or —CF ₃ . In another embodiment are compounds of formula (IIC), wherein n is 2 and each R ₁ is independently Cl or —CF ₃ . In another embodiment are compounds of formula (IIC) wherein n is 1 and R ₁ is halogen. In another embodiment are compounds of formula (IIC) wherein n is 1 and R ₁ is F. In another embodiment are compounds of formula (IIC) wherein n is 1 and R ₁ is Cl. In another embodiment are compounds of formula (IIC), wherein n is 1 and R ₁ is —CF ₃ . In another embodiment are compounds of formula (IIC), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (IIC), wherein n is 1 and R ₁ is CH ₃ . In another embodiment are compounds of formula (IIC) wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment are compounds of formula (IIC) wherein n is 1 and R ₁ is —OCH ₃ . In another embodiment are compounds of formula (IIC) wherein n is 1 and R ₁ is —OCF ₃ . In another embodiment are compounds of formula (IIC) wherein n is 1 and R ₁ is —OCF ₂ H.

  In another embodiment, a compound of formula (IID), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein;

Where
A is a single bond,
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₄ is H, halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (═O) ₂ R _9. , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl substituted, or a substituted or unsubstituted _C 2 -C ₇ heteroaryl, or 2 The of R ₁ together, a substituted or unsubstituted heterocyclic ring, or form a substituted or unsubstituted carbocyclic ring, wherein, when n is 0, R ₄ is not a halogen,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl,
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
J is C (H),
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ Alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C _6- be a C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
m is 2-6,
n is 0-4,
p is 1-3;
q is 1-3.

In one embodiment are compounds of formula (IID), wherein R ₆ is unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment are compounds of formula (IID), wherein R ₆ is substituted C ₂ -C ₇ heterocycloalkyl. In another embodiment are compounds of formula (IID), wherein R ₆ is substituted or unsubstituted morpholinyl. In another embodiment are compounds of formula (IID), wherein R ₆ is substituted or unsubstituted piperazinyl. In another embodiment are compounds of formula (IID), wherein R ₆ is substituted or unsubstituted piperidinyl.

In another embodiment are compounds of formula (IID), wherein R ₅ is halogen. In another embodiment are compounds of formula (IID), wherein R ₅ is —CF ₃ . In another embodiment are compounds of formula (IID), wherein R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (IID), wherein R ₅ is —CH ₃ . In another embodiment are compounds of formula (IID), wherein R ₅ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (IID), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl. In another embodiment are compounds of formula (IID), wherein R ₅ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment are compounds of formula (IID), wherein R ₅ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (IID), wherein R ₅ is substituted or unsubstituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (IID), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There are compounds of (IID). In another embodiment are compounds of formula (IID), wherein R ₂ and R ₃ are each H.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, and , Wherein at least one of R ₂ and R ₃ is not H. In another embodiment are compounds of formula (IID), wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (IID), wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (IID), wherein R ₂ is H and R ₃ is C ₃ -C ₆ cycloalkyl. In another embodiment are compounds of formula (IID), wherein R ₂ is H and R ₃ is cyclopropyl. In another embodiment are compounds of formula (IID), wherein R ₂ is H and R ₃ is cyclopentyl. In another embodiment are compounds of formula (IID), wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (IID), wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (IID), wherein R ₂ is CH ₃ and R ₃ is H. In another embodiment are compounds of formula (IID), wherein R ₂ is C ₃ -C ₆ cycloalkyl and R ₃ is H. In another embodiment are compounds of formula (IID), wherein R ₂ is cyclopropyl and R ₃ is H. In another embodiment are compounds of formula (IID), wherein R ₂ is cyclopentyl and R ₃ is H.

In another embodiment are compounds of formula (IID), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (IID), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment are compounds of formula (IID), wherein R ₂ and R ₃ are joined to form a 6-membered heterocycle.

    In another embodiment are compounds of formula (IID), wherein n is 0.

In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N. _{(R 8) S (= O} ) 2 R 9, S (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O ) R ₉ , —CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} A C ₇ heteroaryl are the compounds of formula (IID). In another embodiment, each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. There is a compound of formula (IID), In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted Or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl Or a substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IID) which are substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IID), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IID), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 2. In another embodiment are compounds of formula (IID), wherein n is 3 and each R ₁ is independently halogen. In another embodiment are compounds of formula (IID), wherein n is 2 and each R ₁ is independently halogen. In another embodiment are compounds of formula (IID), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment are compounds of formula (IID), wherein n is 2 and R ₁ is each F. In another embodiment are compounds of formula (IID), wherein n is 2 and each R ₁ is independently Cl. In another embodiment are compounds of formula (IID), wherein n is 2 and each R ₁ is independently halogen or —CF ₃ . In another embodiment are compounds of formula (IID), wherein n is 2 and each R ₁ is independently F or —CF ₃ . In another embodiment are compounds of formula (IID), wherein n is 2 and each R ₁ is independently Cl or —CF ₃ . In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is halogen. In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is F. In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is Cl. In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is —CF ₃ . In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is CH ₃ . In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is —OCH ₃ . In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is —OCF ₃ . In another embodiment are compounds of formula (IID), wherein n is 1 and R ₁ is —OCF ₂ H.

In another embodiment, R ₄ is H, halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (= O) ₂ R ₉ , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO _{2 R 8, -N (R 8)} 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, or substituted or unsubstituted _C 1 -C ₆ alkoxy, a compound of formula (IID). In another embodiment, R ₄ is H, halogen, —CN, —OH, —OCF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy, There are compounds of formula (IID). In another embodiment are compounds of formula (IID), wherein R ₄ is H. In another embodiment are compounds of formula (IID), wherein R ₄ is halogen. In another embodiment are compounds of formula (IID), wherein R ₄ is F. In another embodiment are compounds of formula (IID), wherein R ₄ is Cl. In another embodiment are compounds of formula (IID), wherein R ₄ is Br. In another embodiment are compounds of formula (IID), wherein R ₄ is —CF ₃ . In another embodiment are compounds of formula (IID), wherein R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IID), wherein R ₄ is —CH ₃ . In another embodiment are compounds of formula (IID), wherein R ₄ is —OCH ₃ .

In another embodiment are compounds of formula (IID), wherein n is 0 and R ₄ is H. In another embodiment are compounds of formula (IID), wherein n is 0 and R ₄ is halogen. In another embodiment are compounds of formula (IID), wherein n is 0 and R ₄ is F. In another embodiment are compounds of formula (IID), wherein n is 0 and R ₄ is Cl. In another embodiment are compounds of formula (IID), wherein n is 0 and R ₄ is Br. In another embodiment are compounds of formula (IID), wherein n is 0 and R ₄ is —CF ₃ . In another embodiment are compounds of formula (IID), wherein n is 0 and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IID), wherein n is 0 and R ₄ is —CH ₃ . In another embodiment are compounds of formula (IID), wherein n is 0 and R ₄ is —OCH ₃ .

In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is Cl, and R ₄ is Cl. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CH ₃ , and R ₄ is Cl. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCH ₃ , and R ₄ is Cl. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CF ₃ , and R ₄ is Cl. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCF ₃ , and R ₄ is Cl. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is Cl, and R ₄ is F. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CH ₃ , and R ₄ is F. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCH ₃ , and R ₄ is F. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CF ₃ , and R ₄ is F. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCF ₃ , and R ₄ is F. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is Cl, and R ₄ is H. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CH ₃ , and R ₄ is H. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCH ₃ , and R ₄ is H. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CF ₃ , and R ₄ is H. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCF ₃ , and R ₄ is H. In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is Cl, and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CH ₃ , and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCH ₃ , and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CF ₃ , and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCF ₃ , and R ₄ is —OCH ₃ . In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is Cl, and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CH ₃ , and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCH ₃ , and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —CF ₃ , and R ₄ is —OCF ₃ . In another embodiment are compounds of formula (IID), wherein n is 1, R ₁ is —OCF ₃ , and R ₄ is —OCF ₃ .

  In another embodiment, a compound of formula (IID '), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein,

Where
A is a single bond,
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₄ is H, F, Cl, Br, I, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, Oh There are two R ₁ together form a substituted or unsubstituted heterocyclic or substituted or unsubstituted carbocyclic ring, wherein, when n is 0, R ₄ is instead Cl,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl,
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
J is C (H),
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ Alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C _6- be a C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
m is 2-6,
n is 0-4,
p is 1-3;
q is 1-3.

  In another aspect, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described herein,

Where
A is a single bond, O, or N (R ₁₀ );
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, a substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ ,-(C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), or

And
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
J is C (H) or N;
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ Alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C _6- be a C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H or C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-5,
p is 1-3;
q is 1-3.

In another embodiment are compounds of formula (III), wherein A is O or N (R ₁₀ ). In another embodiment are compounds of formula (III), wherein A is O, CH ₂ , or N (H). In another embodiment are compounds of formula (III), wherein A is O. In another embodiment are compounds of formula (III), wherein A is N (R ₁₀ ). In another embodiment are compounds of formula (III), wherein A is N (H). In another embodiment are compounds of formula (III), wherein A is N (CH ₃ ). In another embodiment are compounds of formula (III), wherein A is a single bond.

In another embodiment are compounds of formula (III), wherein R ₆ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (III), wherein R ₆ is substituted or unsubstituted cyclopropyl. In another embodiment are compounds of formula (III), wherein R ₆ is substituted or unsubstituted cyclobutyl. In another embodiment are compounds of formula (III), wherein R ₆ is substituted or unsubstituted cyclopentyl. In another embodiment are compounds of formula (III), wherein R ₆ is substituted or unsubstituted cyclohexyl.

In another embodiment are compounds of formula (III), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, R ₆ is substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl, benzothiol Phenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxiadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl, purinyl, furopyridinyl, thienopyridinyl, fluoropyrrolyl, Furofuranyl, thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl, thienothiophenyl, quino There are compounds of formula (III) which are linyl, isoquinolinyl, quinoxalinyl, furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, and benzoisoxazolyl. In another embodiment are compounds of formula (III), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment are compounds of formula (III), wherein R ₆ is substituted pyridyl. In another embodiment are compounds of formula (III), wherein R ₆ is unsubstituted pyridyl.

In another embodiment are compounds of formula (III), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment are compounds of formula (III), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , and R ₁₄ and R ₁₅ are each H. In another embodiment, the compounds of formula (III), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 2, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, the compound of formula (III), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —OH.

In another embodiment, the compounds of formula (III), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 3, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, a compound of formula (III) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —OH.

In another embodiment are compounds of formula (III), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (III). In another embodiment, the compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (III), wherein R ₁₂ is H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is H. There is a compound of III). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (III), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is CH _3. There is a compound of (III). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (III) that forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There are compounds of formula (III) that form. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There are compounds of formula (III) that form.

In another embodiment are compounds of formula (III), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (III). In another embodiment, the compounds of formula (III), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (III), wherein R ₁₂ is H. In another embodiment, the formula ( ₆ ) wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ , and R ₁₂ is H. There is a compound of III). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl, There are compounds of formula (III), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, the formula wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ and R ₁₂ is CH _3. There is a compound of (III). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined together as 5, 6, 7, Or a compound of formula (III) that forms an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 5-membered heterocyclic ring. There are compounds of formula (III) that form. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form a 6-membered heterocyclic ring. There are compounds of formula (III) that form.

In another embodiment are compounds of formula (III), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, R ₆ is

There is a compound of formula (III) In another embodiment, R ₆ is

And a compound of formula (III) wherein J is C (H). In another embodiment, R ₆ is

And a compound of formula (III) wherein J is C (H), p is 1 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (III), wherein J is C (H), p is 2 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (III) wherein J is C (H), p is 3 and q is 1. In another embodiment, R ₆ is

And a compound of formula (III) wherein J is C (H), p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (III), wherein J is C (H), p is 1, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

Are compounds of formula (III), wherein J is C (H), p is 2, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

Are compounds of formula (III), wherein J is C (H), p is 3, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (III), wherein J is C (H), p is 2, q is 2, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment, R ₆ is

And there is a compound of formula (III) wherein J is N. In another embodiment, R ₆ is

And a compound of formula (III) wherein J is N, p is 2 and q is 2. In another embodiment, R ₆ is

There are compounds of formula (III), wherein J is N, p is 2, q is 2, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment are compounds of formula (III), wherein R ₅ is halogen. In another embodiment are compounds of formula (III), wherein R ₅ is —CF ₃ . In another embodiment are compounds of formula (III), wherein R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (III), wherein R ₅ is —CH ₃ . In another embodiment are compounds of formula (III), wherein R ₅ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (III), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl. In another embodiment are compounds of formula (III), wherein R ₅ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (III), wherein R ₅ is substituted or unsubstituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (III), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl.

In another embodiment, the formula, wherein R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There is a compound of (III). In another embodiment are compounds of formula (III), wherein R ₂ and R ₃ are each H.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, and , Wherein at least one of R ₂ and R ₃ is not H. In another embodiment are compounds of formula (III), wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (III), wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (III), wherein R ₂ is H and R ₃ is C ₃ -C ₆ cycloalkyl. In another embodiment are compounds of formula (III), wherein R ₂ is H and R ₃ is cyclopropyl. In another embodiment are compounds of formula (III), wherein R ₂ is H and R ₃ is cyclopentyl. In another embodiment are compounds of formula (III), wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (III), wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (III), wherein R ₂ is CH ₃ and R ₃ is H. In another embodiment are compounds of formula (III), wherein R ₂ is C ₃ -C ₆ cycloalkyl and R ₃ is H. In another embodiment are compounds of formula (III), wherein R ₂ is cyclopropyl and R ₃ is H. In another embodiment are compounds of formula (III) wherein R ₂ is cyclopentyl and R ₃ is H.

In another embodiment are compounds of formula (III), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (III), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment are compounds of formula (III), wherein R ₂ and R ₃ are joined to form a 6-membered heterocycle.

  In another embodiment are compounds of formula (III), wherein n is 0.

In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N. _{(R 8) S (= O} ) 2 R 9, S (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O ) R ₉ , —CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} A C ₇ heteroaryl are the compounds of formula (III). In another embodiment, each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. There is a compound of formula (III) In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted Or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl Or a substituted or unsubstituted C ₆ -C ₁₀ aryl, or a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or a substituted or unsubstituted _C 1 -C ₆ alkoxy, a compound of formula (III). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (III), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (III), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 2. In another embodiment are compounds of formula (III), wherein n is 3 and each R ₁ is independently halogen. In another embodiment are compounds of formula (III), wherein n is 2 and each R ₁ is independently halogen. In another embodiment are compounds of formula (III), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment are compounds of formula (III) wherein n is 2 and each R ₁ is F. In another embodiment are compounds of formula (III), wherein n is 2 and each R ₁ is independently Cl. In another embodiment are compounds of formula (III), wherein n is 2 and each R ₁ is independently halogen or —CF ₃ . In another embodiment are compounds of formula (III), wherein n is 2 and each R ₁ is independently F or —CF ₃ . In another embodiment are compounds of formula (III), wherein n is 2 and each R ₁ is independently Cl or —CF ₃ . In another embodiment are compounds of formula (III) wherein n is 1 and R ₁ is halogen. In another embodiment are compounds of formula (III) wherein n is 1 and R ₁ is F. In another embodiment are compounds of formula (III) wherein n is 1 and R ₁ is Cl. In another embodiment are compounds of formula (III) wherein n is 1 and R ₁ is —CF ₃ . In another embodiment are compounds of formula (III), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (III), wherein n is 1 and R ₁ is CH ₃ . In another embodiment are compounds of formula (III), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment are compounds of formula (III) wherein n is 1 and R ₁ is —OCH ₃ . In another embodiment are compounds of formula (III) wherein n is 1 and R ₁ is —OCF ₃ . In another embodiment are compounds of formula (III), wherein n is 1 and R ₁ is —OCF ₂ H.

  In another aspect, described herein is a compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

In the formula:
A is a single bond, O, or N (R ₁₀ );
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, -S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, - CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted C ₂ -C ₇ heteroaryl Is;
Or two R ₁ together form a substituted or unsubstituted heterocycle, or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl; or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle;
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} It is -C ₇ heteroaryl;
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ ,-(C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ )), or

Is;
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl; or R ₁₁ and R ₁₂ are taken together as a 5-membered, 6-membered, 7-membered, Or form an 8-membered heterocycle;
J is C (H) or N;
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or a substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl;
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
Or R ₁₄ and R ₁₅ together form a 4-, 5-, or 6-membered cycloalkyl ring;
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ Alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C _6- be a C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H or C ₁ -C ₄ alkyl;
m is 2-6;
n is 0-5;
p is 1-3;
q is 1-3.

In another embodiment are compounds of formula (IV), wherein A is O or N (R ₁₀ ). In another embodiment are compounds of formula (IV), wherein A is O or N (H). In another embodiment are compounds of formula (IV), wherein A is 0. In another embodiment are compounds of formula (IV), wherein A is N (R ₁₀ ). In another embodiment are compounds of formula (IV), wherein A is N (H). In another embodiment are compounds of formula (IV), wherein A is N (CH ₃ ). In another embodiment are compounds of formula (IV), wherein A is a single bond.

In another embodiment are compounds of formula (IV), wherein R ₆ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (IV), wherein R ₆ is substituted or unsubstituted cyclopropyl. In another embodiment are compounds of formula (IV), wherein R ₆ is substituted or unsubstituted cyclobutyl. In another embodiment are compounds of formula (IV), wherein R ₆ is substituted or unsubstituted cyclopentyl. In another embodiment are compounds of formula (IV), wherein R ₆ is substituted or unsubstituted cyclohexyl.

In another embodiment are compounds of formula (IV), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, the compound of formula (IV), wherein R ₆ is substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, Pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolipyridinyl, imidazopyridinyl Pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl, purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl, thienofuranyl, 1,4-dihydropyrrolopyrrolyl , Thienopyrrolyl, thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl, furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, and benzoisoxazolyl. In another embodiment are compounds of formula (IV), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment are compounds of formula (IV), wherein R ₆ is substituted pyridyl. In another embodiment are compounds of formula (IV), wherein R ₆ is unsubstituted pyridyl.

In another embodiment are compounds of formula (IV), wherein R ₆ is-(C (R ₁₄ ) (R ₁₅ ) _m R _{21. In} another embodiment, R ₆ is-(C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ and there is a compound of formula (IV)) wherein R ₁₄ and R ₁₅ are each H. In another embodiment, the compounds of formula (IV), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 2, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, a compound of formula (IV) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —OH.

In another embodiment, the compounds of formula (IV), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 3, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, of Formula (IV), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, a compound of formula (IV) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —OH.

In another embodiment are compounds of formula (IV), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (IV). In another embodiment, the compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IV), wherein R ₁₂ is H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is H. There is a compound of IV). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IV), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, the formula wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ and R ₁₂ is CH _3. There is a compound of (IV). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form 5 members, 6 members, 7 There are compounds of formula (IV) which form a member, or an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ together form a 5-membered heterocyclic ring. There is a compound of formula (IV). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ together form a 6-membered heterocyclic ring. There is a compound of formula (IV).

In another embodiment are compounds of formula (IV), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (IV). In another embodiment, the compounds of formula (IV), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IV), wherein R ₁₂ is H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ , and R ₁₂ is H. There is a compound of IV). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (IV), wherein R ₁₂ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, the formula, wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ , and R ₁₂ is CH _3. There is a compound of (IV). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form 5 members, 6 members, 7 There are compounds of formula (IV) which form a member, or an 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ together form a 5-membered heterocyclic ring. There is a compound of formula (IV). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ together form a 6-membered heterocyclic ring. There is a compound of formula (IV).

In another embodiment are compounds of formula (IV), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, R ₆ is

There is a compound of formula (IV) In another embodiment, R ₆ is

And a compound of formula (IV) wherein J is C (H). In another embodiment, R ₆ is

And a compound of formula (IV) wherein J is C (H), p is 1 and q is 1. In another embodiment, R ₆ is

And a compound of formula (IV) wherein J is C (H), p is 2 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (IV), wherein J is C (H), p is 3 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (IV) wherein J is C (H), p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (IV), wherein J is C (H), p is 1, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (IV), wherein J is C (H), p is 2, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (IV), wherein J is C (H), p is 3, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (IV), wherein J is C (H), p is 2, q is 2, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment, R ₆ is

And a compound of formula (IV) wherein J is N. In another embodiment, R ₆ is

And a compound of formula (IV) wherein J is N, p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (IV), wherein J is N, p is 2, q is 2, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment are compounds of formula (IV), wherein R ₅ is halogen. In another embodiment are compounds of formula (IV), wherein R ₅ is —CF ₃ . In another embodiment are compounds of formula (IV), wherein R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, _{R 5} is -CH _3, the compound of formula (IV) is provided. In another embodiment are compounds of formula (IV), wherein R ₅ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (IV), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl. In another embodiment are compounds of formula (IV), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, _{R 5} is _C 3 -C ₈ cycloalkyl substituted or unsubstituted compound of formula (IV) is provided. In another embodiment are compounds of formula (IV), wherein R ₅ is substituted or unsubstituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (IV), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There is a compound of (IV). In another embodiment are compounds of formula (IV), wherein R ₂ and R ₃ are each H.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl; And there is a compound of formula (IV) wherein at least one of R ₂ and R ₃ is not H. In another embodiment are compounds of formula (IV), wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (IV), wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (IV), wherein R ₂ is H and R ₃ is C ₃ -C ₆ cycloalkyl. In another embodiment are compounds of formula (IV), wherein R ₂ is H and R ₃ is cyclopropyl. In another embodiment are compounds of formula (IV), wherein R ₂ is H and R ₃ is cyclopentyl. In another embodiment are compounds of formula (IV), wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (IV), wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (IV), wherein R ₂ is CH ₃ and R ₃ is H. In another embodiment are compounds of formula (IV), wherein R ₂ is C ₃ -C ₆ cycloalkyl and R ₃ is H. In another embodiment are compounds of formula (IV), wherein R ₂ is cyclopropyl and R ₃ is H. In another embodiment are compounds of formula (IV), wherein R ₂ is cyclopentyl and R ₃ is H.

In another embodiment are compounds of formula (IV), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (IV), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment are compounds of formula (IV), wherein R ₂ and R ₃ together form a 6 membered heterocycle.

  In another embodiment are compounds of formula (IV), wherein n is 0.

In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S. _{(= O) 2 R 9,} -S (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, _{-CO 2 R 8, -N (R} 8) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C _3- C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ f, A Roariru are the compounds of formula (IV). In another embodiment, each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. A compound of formula (IV) is provided. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted Or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl , substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl are the compounds of formula (IV). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or a substituted or unsubstituted _C 1 -C ₆ alkoxy, a compound of formula (IV). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IV), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (IV), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 2. In another embodiment, there is provided a compound of formula (IV), wherein n is 3 and each R ₁ is independently halogen. In another embodiment, there is provided a compound of formula (IV), wherein n is 2 and each R ₁ is independently halogen. In another embodiment, there is provided a compound of formula (IV), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment, there is provided a compound of formula (IV), wherein n is 2 and R ₁ is each F. In another embodiment, there is provided a compound of formula (IV), wherein n is 2 and each R ₁ is independently Cl. In another embodiment, there is provided a compound of formula (IV), wherein n is 2 and each R ₁ is independently halogen or CF ₃ . In another embodiment, there is provided a compound of formula (IV), wherein n is 2 and each R ₁ is independently F or CF ₃ . In another embodiment, provided is a compound of formula (IV), wherein n is 2 and each R ₁ is independently Cl or CF ₃ . In another embodiment, there is provided a compound of formula (IV), wherein n is 1 and R ₁ is halogen. In another embodiment, provided is a compound of formula (IV), wherein n is 1 and R ₁ is F. In another embodiment, provided is a compound of formula (IV), wherein n is 1 and R ₁ is Cl. In another embodiment, provided is a compound of formula (IV), wherein n is 1 and R ₁ is —CF ₃ . In another embodiment, there is provided a compound of formula (IV), wherein n is 1 and R ₁ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, provided is a compound of formula (IV), wherein n is 1 and R ₁ is CH ₃ . In another embodiment, there is provided a compound of formula (IV), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment, provided is a compound of formula (IV), wherein n is 1 and R ₁ is -OCH ₃ . In another embodiment, provided is a compound of formula (IV), wherein n is 1 and R ₁ is -OCF ₃ . In another embodiment, provided is a compound of formula (IV), wherein n is 1 and R ₁ is —OCF ₂ H.

  In another aspect, described herein is a compound of formula (V), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

In the formula:
A is a single bond, O, or N (R ₁₀ );
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, -S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, - CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted C ₂ -C ₇ heteroaryl Is;
Or two R ₁ together form a substituted or unsubstituted heterocycle, or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl; or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle;
R ₅ is halogen, —CN, —OH, —CF ₃ , unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl. Substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted C ₂ -C ₇ heteroaryl;
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ ,-(C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ )), or

Is;
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl; or R ₁₁ and R ₁₂ are taken together as a 5-membered, 6-membered, 7-membered, Or form an 8-membered heterocycle;
J is C (H) or N;
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or a substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl;
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl; or R ₁₄ and R ₁₅ together, 4-membered, 5-membered, or 6-membered A cycloalkyl ring of
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ Alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C _6- be a C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H or C ₁ -C ₄ alkyl;
m is 2-6;
n is 0-5;
p is 1-3;
q is 1-3.

In another embodiment are compounds of formula (V), wherein A is O or N (R ₁₀ ). In another embodiment are compounds of formula (V), wherein A is O or N (H). In another embodiment are compounds of formula (V), wherein A is O. In another embodiment are compounds of formula (V), wherein A is N (R ₁₀ ). In another embodiment are compounds of formula (V), wherein A is N (H). In another embodiment are compounds of formula (V), wherein A is N (CH ₃ ). In another embodiment are compounds of formula (V), wherein A is a single bond.

In another embodiment are compounds of formula (V), wherein R ₆ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (V), wherein R ₆ is substituted or unsubstituted cyclopropyl. In another embodiment are compounds of formula (V), wherein R ₆ is substituted or unsubstituted cyclobutyl. In another embodiment are compounds of formula (V), wherein R ₆ is substituted or unsubstituted cyclopentyl. In another embodiment are compounds of formula (V), wherein R ₆ is substituted or unsubstituted cyclohexyl.

In another embodiment are compounds of formula (V), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, the compound of formula (V), wherein R ₆ is substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, Pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolipyridinyl, imidazopyridinyl Pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl, purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl, thienofuranyl, 1,4-dihydropyrrolopyrrolyl, Thienopyrrolyl, thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl, furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, and benzoisoxazolyl. In another embodiment are compounds of formula (V), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment are compounds of formula (V), wherein R ₆ is substituted pyridyl. In another embodiment are compounds of formula (V), wherein R ₆ is unsubstituted pyridyl.

In another embodiment are compounds of formula (V), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment are compounds of formula (V), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , and R ₁₄ and R ₁₅ are each H. In another embodiment, the compounds of formula (V), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 2, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, of Formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, the compound of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is substituted or unsubstituted phenyl.
In another embodiment, the compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —OH.

In another embodiment, the compounds of formula (V), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 3, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment, the compound of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₆ -C ₁₀ aryl. is there. In another embodiment are compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is substituted or unsubstituted phenyl. In another embodiment, the compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —OH.

In another embodiment are compounds of formula (V), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (V). In another embodiment, the compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (V), wherein R ₁₂ is H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ , and R ₁₂ is H. V) is a compound. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (V), wherein R ₁₂ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, the formula wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, R ₁₁ is CH ₃ and R ₁₂ is CH _3. There is a compound of (V). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ are combined to form 5 members, 6 members, 7 There are compounds of formula (V) that form a membered or 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ together form a 5-membered heterocyclic ring. There is a compound of formula (V). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 2, and R ₁₁ and R ₁₂ together form a 6-membered heterocyclic ring. There is a compound of formula (V).

In another embodiment are compounds of formula (V), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ). In another embodiment, R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₄ and R ₁₅ are each H. There is a compound of formula (V). In another embodiment, the compounds of formula (V), wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are each H. There is. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (V), wherein R ₁₂ is H. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ , and R ₁₂ is H. V) is a compound. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ is substituted or unsubstituted C ₁ -C ₆ alkyl; There are compounds of formula (V), wherein R ₁₂ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, the formula, wherein R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, R ₁₁ is CH ₃ , and R ₁₂ is CH _3. There is a compound of (V). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ are combined to form 5 members, 6 members, 7 There are compounds of formula (V) that form a membered or 8-membered heterocycle. In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ together form a 5-membered heterocyclic ring. There is a compound of formula (V). In another embodiment, R ₆ is — (CH ₂ ) _m N (R ₁₁ ) (R ₁₂ ), m is 3, and R ₁₁ and R ₁₂ together form a 6-membered heterocyclic ring. There is a compound of formula (V).

In another embodiment are compounds of formula (V), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, R ₆ is

There is a compound of formula (V) In another embodiment, R ₆ is

And there is a compound of formula (V), wherein J is C (H). In another embodiment, R ₆ is

And a compound of formula (V) wherein J is C (H), p is 1 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (V), wherein J is C (H), p is 2 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (V), wherein J is C (H), p is 3 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (V), wherein J is C (H), p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (V), wherein J is C (H), p is 1, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (V), wherein J is C (H), p is 2, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (V), wherein J is C (H), p is 3, q is 1 and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (V), wherein J is C (H), p is 2, q is 2, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment, R ₆ is

And a compound of formula (V) wherein J is N. In another embodiment, R ₆ is

There is a compound of formula (V), wherein J is N, p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (V), wherein J is N, p is 2, q is 2, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment are compounds of formula (V), wherein R ₅ is halogen. In another embodiment are compounds of formula (V), wherein R ₅ is —CF ₃ . In another embodiment are compounds of formula (V), wherein R ₅ is unsubstituted C ₁ -C ₆ alkyl. In another embodiment, provided is a compound of formula (V), wherein R ₅ is —CH ₃ . In another embodiment are compounds of formula (V), wherein R ₅ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (V), wherein R ₅ is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl. In another embodiment are compounds of formula (V), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, there is provided a compound of formula (V), wherein R ₅ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (V), wherein R ₅ is substituted or unsubstituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (V), wherein R ₅ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl. There is a compound of (V). In another embodiment are compounds of formula (V), wherein R ₂ and R ₃ are each H.

In another embodiment, R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl; And there is a compound of formula (V) wherein at least one of R ₂ and R ₃ is not H. In another embodiment are compounds of formula (V), wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (V), wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (V), wherein R ₂ is H and R ₃ is C ₃ -C ₆ cycloalkyl. In another embodiment are compounds of formula (V), wherein R ₂ is H and R ₃ is cyclopropyl. In another embodiment are compounds of formula (V), wherein R ₂ is H and R ₃ is cyclopentyl. In another embodiment are compounds of formula (V), wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (V), wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (V), wherein R ₂ is CH ₃ and R ₃ is H. In another embodiment are compounds of formula (V), wherein R ₂ is C ₃ -C ₆ cycloalkyl and R ₃ is H. In another embodiment are compounds of formula (V), wherein R ₂ is cyclopropyl and R ₃ is H. In another embodiment are compounds of formula (V), wherein R ₂ is cyclopentyl and R ₃ is H.

In another embodiment are compounds of formula (V), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (V), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment are compounds of formula (V), wherein R ₂ and R ₃ together form a 6-membered heterocycle.

  In another embodiment are compounds of formula (V), wherein n is 0.

In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S. _{(= O) 2 R 9,} -S (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, _{-CO 2 R 8, -N (R} 8) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C _3- C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ f, A Roariru are the compounds of formula (V). In another embodiment, each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. A compound of formula (V) is provided. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted Or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl Or a substituted or unsubstituted C ₆ -C ₁₀ aryl, or a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (V) which are substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (V), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or There are compounds of formula (V), which are substituted or unsubstituted C ₁ -C ₆ alkoxy and n is 2. In another embodiment, there is provided a compound of formula (V), wherein n is 3 and each R ₁ is independently halogen. In another embodiment, there is provided a compound of formula (V), wherein n is 2 and each R ₁ is independently halogen. In another embodiment, there is provided a compound of formula (V), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment, there is provided a compound of formula (V), wherein n is 2 and R ₁ is each F. In another embodiment, there is provided a compound of formula (V), wherein n is 2 and each R ₁ is independently Cl. In another embodiment, there is provided a compound of formula (V), wherein n is 2 and each R ₁ is independently halogen or CF ₃ . In another embodiment, there is provided a compound of formula (V), wherein n is 2 and each R ₁ is independently F or CF ₃ . In another embodiment, there is provided a compound of formula (V), wherein n is 2 and each R ₁ is independently Cl or CF ₃ . In another embodiment, there is provided a compound of formula (V), wherein n is 1 and R ₁ is halogen. In another embodiment, provided is a compound of formula (V), wherein n is 1 and R ₁ is F. In another embodiment, there is provided a compound of formula (V), wherein n is 1 and R ₁ is Cl. In another embodiment, provided is a compound of formula (V), wherein n is 1 and R ₁ is —CF ₃ . In another embodiment, there is provided a compound of formula (V), wherein n is 1 and R ₁ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, provided is a compound of formula (V), wherein n is 1 and R ₁ is CH ₃ . In another embodiment, there is provided a compound of formula (V), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment, provided is a compound of formula (V), wherein n is 1 and R ₁ is —OCH ₃ . In another embodiment, provided is a compound of formula (V), wherein n is 1 and R ₁ is —OCF ₃ . In another embodiment, provided is a compound of formula (V), wherein n is 1 and R ₁ is —OCF ₂ H.

  In another aspect, described herein is a compound of formula (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

In the formula:
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, -S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, - CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted C ₂ -C ₇ heteroaryl Is;
Or two R ₁ together form a substituted or unsubstituted heterocycle, or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H or C ₁ -C ₄ alkyl; or R ₂ and R ₃ together form a 5- or 6-membered heterocycle;
R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₆ is unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl,-(C (R <_14> ) (R <_15> )) _mR <_21> ,

Is;
J is C (H);
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or a substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl;
R ₁₄ and R ₁₅ are each independently H, halogen, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroaryl alkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl or substituted or unsubstituted _C 2 -C ₇ heteroaryl;
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H;
m is 2-6;
n is 0-5;
p is 1-3;
q is 1-3.

In another embodiment are compounds of formula (VI), wherein R ₆ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In another embodiment are compounds of formula (VI), wherein R ₆ is substituted or unsubstituted cyclopropyl. In another embodiment are compounds of formula (VI), wherein R ₆ is substituted or unsubstituted cyclobutyl. In another embodiment are compounds of formula (VI), wherein R ₆ is substituted or unsubstituted cyclopentyl. In another embodiment are compounds of formula (VI), wherein R ₆ is substituted or unsubstituted cyclohexyl.

In another embodiment are compounds of formula (VI), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, the compound of formula (VI), wherein R ₆ is substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, Pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolipyridinyl, imidazopyridinyl Pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl, purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl, thienofuranyl, 1,4-dihydropyrrolopyrrolyl , Thienopyrrolyl, thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl, furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, and benzoisoxazolyl. In another embodiment are compounds of formula (VI), wherein R ₆ is substituted or unsubstituted pyridyl. In another embodiment are compounds of formula (VI), wherein R ₆ is substituted pyridyl. In another embodiment are compounds of formula (VI), wherein R ₆ is unsubstituted pyridyl.

In another embodiment, compounds of formula (VI) are provided, wherein R ₆ is unsubstituted C ₁ -C ₄ alkyl. In another embodiment, there is provided a compound of formula (VI), wherein R ₆ is —CH ₃ . In another embodiment are compounds of formula (VI), wherein R ₆ is —CH ₂ CH ₃ . In another embodiment are compounds of formula (VI), wherein R ₆ is —CH ₂ CH ₂ CH ₃ .

In another embodiment are compounds of formula (VI), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ . In another embodiment are compounds of formula (VI), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , and R ₁₄ and R ₁₅ are each H or halogen. In another embodiment are compounds of formula (VI), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , and R ₁₄ and R ₁₅ are each H or halogen. In another embodiment, the compounds of formula (VI), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 2, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, of Formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —OH. In another embodiment, Formula (VI) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —N (R ₂₂ ) S (═O) ₂ R _23. There is a compound. In another embodiment, the compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —N (H) S (═O) 2 CH ₃ . There is. In another embodiment, of Formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —N (R ₂₂ ) C (═O) R ₂₃ . There are compounds. In another embodiment, the compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —N (H) C (═O) CH ₃ . There is. In another embodiment, the compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —C (═O) N (R ₂₂ ) ₂ . There is. In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —C (═O) NH ₂ . In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —CO ₂ R ₂₂ . In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 2, and R ₂₁ is —CO ₂ Et.

In another embodiment, the compounds of formula (VI), wherein R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , m is 3, and R ₁₄ and R ₁₅ are each H. There is. In another embodiment, of Formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. There are compounds. In another embodiment, the compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl. There is. In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted C ₆ -C ₁₀ aryl. In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is substituted phenyl. In another embodiment, the compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is a substituted or unsubstituted C ₂ -C ₇ heteroaryl. There is. In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —OH. In another embodiment, Formula (VI) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —N (R ₂₂ ) S (═O) ₂ R _23. There are compounds. In another embodiment, the compounds of formula (VI) wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —N (H) S (═O) 2 CH ₃ . There is. In another embodiment, of Formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —N (R ₂₂ ) C (═O) R ₂₃ . There are compounds. In another embodiment, the compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —N (H) C (═O) CH ₃ . There is. In another embodiment, the compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —C (═O) N (R ₂₂ ) ₂ . There is. In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —C (═O) NH ₂ . In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —CO ₂ R ₂₂ . In another embodiment are compounds of formula (VI), wherein R ₆ is — (CH ₂ ) _m R ₂₁ , m is 3, and R ₂₁ is —CO ₂ Et.

In another embodiment are compounds of formula (VI), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, R ₆ is

And a compound of formula (VI) wherein J is C (H). In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 1 and q is 1. In another embodiment, R ₆ is

And a compound of formula (VI) wherein J is C (H), p is 2 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (VI) wherein J is C (H), p is 3 and q is 1. In another embodiment, R ₆ is

And a compound of formula (VI) wherein J is C (H), p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 1, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 2, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 3, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 2, q is 2, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment are compounds of formula (VI), wherein R ₆ is a substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl. In another embodiment, R ₆ is

And a compound of formula (VI) wherein J is C (H). In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 1 and q is 1. In another embodiment, R ₆ is

And a compound of formula (VI) wherein J is C (H), p is 2 and q is 1. In another embodiment, R ₆ is

There is a compound of formula (VI) wherein J is C (H), p is 3 and q is 1. In another embodiment, R ₆ is

And a compound of formula (VI) wherein J is C (H), p is 2 and q is 2. In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 1, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 2, q is 1, and R ₁₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 3, q is 1, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, R ₆ is

There is a compound of formula (VI), wherein J is C (H), p is 2, q is 2, and R ₁₃ is substituted or unsubstituted C ₁ -C ₆ alkyl.

In another embodiment are compounds of formula (VI), wherein R ₅ is substituted C ₁ -C ₆ alkyl. In another embodiment are compounds of formula (VI), wherein R ₅ is unsubstituted C ₁ -C ₆ alkyl. In another embodiment, provided is a compound of formula (VI), wherein R ₅ is unsubstituted —CH ₃ . In another embodiment are compounds of formula (VI), wherein R ₅ is unsubstituted —CH ₂ CH ₃ .

In another embodiment are compounds of formula (VI), wherein R ₂ and R ₃ are each H. In another embodiment, a compound of formula (VI) wherein R ₂ and R ₃ are each independently H or C ₁ -C ₄ alkyl; and at least one of R ₂ and R ₃ is not H is there. In another embodiment are compounds of formula (VI), wherein R ₂ is H and R ₃ is C ₁ -C ₄ alkyl. In another embodiment are compounds of formula (VI), wherein R ₂ is H and R ₃ is CH ₃ . In another embodiment are compounds of formula (VI), wherein R ₂ is CH ₃ and R ₃ is CH ₃ . In another embodiment are compounds of formula (VI), wherein R ₂ is C ₁ -C ₄ alkyl and R ₃ is H. In another embodiment are compounds of formula (VI) wherein R ₂ is CH ₃ and R ₃ is H.

In another embodiment are compounds of formula (VI), wherein R ₂ and R ₃ together form a 5 or 6 membered heterocycle. In another embodiment are compounds of formula (VI), wherein R ₂ and R ₃ together form a 5-membered heterocycle. In another embodiment are compounds of formula (VI), wherein R ₂ and R ₃ together form a 6 membered heterocycle.

  In another embodiment are compounds of formula (VI), wherein n is 0.

In another embodiment, each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCF ₂ H, —CF ₃ , SR8, —N (R ₈ ) S (= _{O) 2 R 9, -S (} = O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, A reel are the compounds of formula (VI). In another embodiment, each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. A compound of formula (VI) is provided. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted. C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted There are compounds of formula (VI) that are substituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted C ₂ -C ₇ heteroaryl. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted. it is a _C 1 -C ₆ alkoxy, a compound of formula (VI). In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted. There are compounds of formula (VI), wherein C ₁ -C ₆ alkoxy is n and n is 3. In another embodiment, each R ₁ is independently halogen, —CN, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted. There are compounds of formula (VI), wherein C ₁ -C ₆ alkoxy is n and n is 2. In another embodiment, there is provided a compound of formula (VI), wherein n is 3 and each R ₁ is independently halogen. In another embodiment, there is provided a compound of formula (VI), wherein n is 2 and each R ₁ is independently halogen. In another embodiment, there is provided a compound of formula (VI), wherein n is 2 and each R ₁ is independently F or Cl. In another embodiment, provided is a compound of formula (VI), wherein n is 2, _one of R ₁ is F, and _one of R ₁ is —CF ₃ . In another embodiment, there is provided a compound of formula (VI), wherein n is 2 and R ₁ is each F. In another embodiment, there is provided a compound of formula (VI), wherein n is 2 and R ₁ is each Cl. In another embodiment, provided is a compound of Formula (VI), wherein n is 2, _one of R ₁ is F, and _one of R ₁ is Cl. In another embodiment, there is provided a compound of formula (VI), wherein n is 1 and R ₁ is halogen. In another embodiment, provided is a compound of formula (VI), wherein n is 1 and R ₁ is F. In another embodiment, there is provided a compound of formula (VI), wherein n is 1 and R ₁ is Cl. In another embodiment, there is provided a compound of formula (VI), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, provided is a compound of formula (VI), wherein n is 1 and R ₁ is CH ₃ . In another embodiment, provided is a compound of formula (VI), wherein n is 1 and R ₁ is -CF ₃ . In another embodiment, there is provided a compound of formula (VI), wherein n is 1 and R ₁ is substituted or unsubstituted C ₁ -C ₆ alkoxy. In another embodiment, provided is a compound of formula (VI), wherein n is 1 and R ₁ is -OCH ₃ . In another embodiment, provided is a compound of formula (VI), wherein n is 1 and R ₁ is —OCF ₃ . In another embodiment, provided is a compound of formula (VI), wherein n is 1 and R ₁ is —OCF ₂ H.

  In another embodiment is a compound selected from the following formulas, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

Deuterium (D or ² H) is a stable non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen usually occurs as a mixture of isotopes ¹ H (hydrogen or protium), D ( ² H or deuterium), and T ( ³ H or tritium). The natural abundance of deuterium is 0.015%. Usually, in chemical compounds having H atoms, the H atoms actually represent a mixture of H and D, with about 0.015% being D. In some embodiments, deuterium-rich compounds described herein are achieved by exchanging protons for deuterium or via deuterium-rich starting materials and / or intermediates.

  Any combination of groups described above for the various variations is contemplated herein.

  Throughout this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.

<Further Form of Compound>
The compounds described herein may optionally exist as diastereomers, enantiomers, or other stereoisomers. The compounds presented herein include diastereomeric, enantiomeric, and epimeric forms as well as all suitable mixtures thereof. Separation of stereoisomers may be carried out by chromatography or diastereomeric formation and by recrystallization or chromatography or any combination thereof. (See Jean Jacques, Andrew Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 198, which is incorporated herein by reference for its disclosure.) Stereoisomers may also be obtained by stereoselective synthesis.

  In some situations, the compounds may exist as tautomers. All tautomers are included within the formulas described herein.

  The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, active metabolites of such compounds with the same type of activity are within the scope of this disclosure. In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water and ethanol. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

  In some embodiments, the compounds described herein may be prepared as prodrugs. “Prodrug” refers to an agent that is converted into the parent drug in vivo. In some situations, prodrugs are often useful because they can be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, but not the parent drug. Prodrugs can also have improved solubility in pharmaceutical compositions over the parent drug. An example of a prodrug is, but is not limited to, a compound as described herein, which uses esters (“prodrugs” to facilitate transmission across cell membranes where water solubility is detrimental to mobility. )), But then metabolically hydrolyzed to the carboxylic acid, the active form, once water solubility has entered the beneficial cells. A further example of a prodrug may be a short peptide (polyamino acid) linked to an acid group that reveals the active moiety as the peptide is metabolized. In certain embodiments, after in vivo administration, the prodrug is chemically converted to the biological, pharmaceutical, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized into a biological, pharmaceutical, or therapeutically active form of the compound by one or more steps or processes.

  To produce a prodrug, the pharmaceutically active compound is modified such that the active compound is regenerated after administration in vivo. Prodrugs may be designed to alter the metabolic stability or transport properties of a drug, cover side effects or toxicity, improve the flavor of a drug, or alter other properties or characteristics of a drug it can. In some embodiments, once a pharmaceutically active compound is determined by knowledge of the pharmacodynamic process and in vivo drug metabolism, a prodrug of the compound is designed. (For example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985; Roseboom et al., Pharmalogic. l Reviews, 56: 53-102, 2004; Miller et al., J. Med.Chem.Vol.46, no.24, 5097-5116, 2003; Aesop Cho, "Recent Advances in OralProdruDr. in Medicinal Chemistry, Vol. 41, 395-407, 2006).

  The prodrug is of the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or as described herein Prodrug forms of the compounds described herein that are metabolized in vivo to yield compounds of (VI) are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs for another derivative or active compound.

  In some situations, prodrugs are often useful because they can be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, but not the parent drug. Prodrugs can also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives for use as modulators that enhance drug delivery to site-specific tissues. In some embodiments, the prodrug design increases effective water solubility. See, for example, Fedorak et al. , Am. J. et al. Physiol. , 269: G210-218 (1995); McLoed et al. , Gastroenterol, 106: 405-413 (1994); Hochhaus et al. , Biomed. Chrom. 6: 283-286 (1992); Larsen and H.M. Bundgaard, Int. J. et al. J. Pharmaceuticals, 37, 87 (1987); Larsen et al. , Int. J. et al. Pharmaceutics, 47, 103 (1988); Sinkula et al. , J. et al. Pharm. Sci. 64: 181-210 (1975); Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.E. C. S. Symposium Series; and Edward B. See Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein for such disclosure.

  The sites on the aromatic ring moieties of the compounds described herein are sensitive to various metabolic reactions and therefore, by way of example only, incorporation of appropriate substituents on aromatic ring structures such as halogens. Can reduce, minimize, or eliminate this metabolic pathway.

  The compounds described herein may be labeled isotopically (eg, with a radioactive isotope) or by other means, including chromophores or fluorescent moieties, bioluminescent Labels, photoexcitable or chemiluminescent labels include but are not limited to.

The compounds described herein include isotopically labeled compounds wherein one or more atoms have an atomic mass or mass number different from the atomic mass or mass number normally found in nature Unless otherwise replaced, the compounds are the same as listed in the various formulas and structures presented herein. Examples of isotopes that can be incorporated into the compounds are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, respectively. , ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁶ Cl, and the like. Certain isotopically labeled compounds described herein, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and / or substrate tissue distribution assays. Furthermore, deuterium, i.e. substitution with isotopes such as ^{2 H,} for example, can result in certain therapeutic advantages resulting such reduction of increase or dosage requirements vivo half-life, from greater metabolic stability it can.

  In additional or further embodiments, the compounds described herein are metabolized after administration to an organism in need to produce a metabolite, which is used later for desired The desired effects including the therapeutic effects of

  The compounds described herein may be formed and / or used as pharmaceutically acceptable salts. The types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts wherein the free base form of the compound is pharmaceutically acceptable: eg hydrochloric acid, hydrobromic acid, sulfuric acid, phosphorus Or an inorganic acid such as acid or metaphosphoric acid; or, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tri Fluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid , Benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1- Rubonic acid, glucoheptonic acid, 4,4′-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid Acid addition salts formed by reacting with organic acids such as glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, ethanesulfonic acid, phenylbutyric acid, valproic acid; (2) When an acidic proton is present in the parent compound, the compound is replaced by a metal ion such as an alkali metal ion (eg, lithium, sodium, potassium), alkaline earth ion (eg, magnesium or calcium), or aluminum, a salt including. In some cases, the compounds described herein are in harmony with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris (hydroxymethyl) methylamine. Sometimes. In other cases, the compounds described herein may form salts with amino acids such as, but not limited to, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.

  It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates include either stoichiometric or non-stoichiometric amounts of solvent and may be formed during the process of crystallization using a pharmaceutically acceptable solvent such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated forms as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

  In some embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI) Etc., the compounds described herein are in various forms including, but not limited to, amorphous forms, crushed forms, and nanoparticulate forms. In addition, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, and storage temperature can cause dominant single crystal morphology.

  Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates include, but are not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor adsorption, and microscopy. May be accomplished using various techniques. Thermal analysis methods address thermochemical decomposition or thermal physical processes including, but not limited to polymorphic transitions, and the methods analyze weight relationships to analyze associations between polymorphs. Used for finding glass transition temperature, or for studies adapted to excipients. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulation differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric and infrared analysis (Thermogravimetric). and Infrared analysis) (TG / IR). X-ray diffraction methods include but are not limited to single crystal and powder diffractometers and synchrotron sources. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UV-VIS, and NMR (liquid and solid state). Various microscopy techniques include polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy with EDX (in a gas or water vapor atmosphere), IR Including but not limited to microscopy and Raman microscopy.

  Throughout this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.

<Synthesis of compounds>
In some embodiments, the synthesis of the compounds described herein is accomplished using means described in the chemical literature, using the methods described herein, or combinations thereof. The In addition, the solvents, temperatures, and other reaction conditions presented herein can vary.

  In some embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI) Is prepared according to the synthetic route shown in Scheme 1.

As shown in the schematic diagram 1, urea is obtained by adding an amine to an isocyanate.

  Through a similar protocol, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI) is Prepared as shown in Scheme 2.

In some embodiments, synthetic intermediates of isocyanate and amine are prepared according to Schemes 3-4.

  In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fisher Chemicals), and Acros Organics. Or is derived from it.

  In further embodiments, the compounds described herein, and other related compounds having different substituents, can be prepared from the techniques and materials described herein, as well as the art as described below. For example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, Co., Ltd., United States; Rodd's Chemistry of Carbon 5). (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and) Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed. (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed. , Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS in ORGANIC SYNTHESIS 3rd Ed. , (Wiley 1999), all of which are incorporated by reference for such disclosure.

<Specific terminology>
Unless defined otherwise, all terms and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. Where there are multiple definitions of terms herein, those in this section prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences referred to herein (eg, sequences available in GenBank or other databases) are incorporated by reference. Where URLs or other such identifiers or addresses are mentioned, such identifiers may change and certain information on the Internet may appear or disappear, but equivalent information can be retrieved by Internet search. It is understood that it can be discovered. Reference to it evidences the availability and public dissemination of such information.

  It should be understood that the foregoing general description and the following detailed description are exemplary and exemplary only and are not restrictive of any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. As used in the specification and appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. It must be noted. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” is not limiting, as are other forms such as “included”, “includes”, and “included”.

  The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Definitions of standard chemical terms include, but are not limited to “Carey and Sundberg” ADVANCED ORGANIC CHEMISTRY 4TH ED. Vols. A (2000) and B (2001), Plenum Press, New York ". Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPCL, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology exist.

  Unless otherwise defined, the nomenclature used in combination with the analytical chemistry, synthetic organic chemistry, medicinal chemistry, and medicinal chemistry described herein, and their testing methods and techniques are described in the art. It is recognized in the field. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, tissue culture and transformation (eg, electroporation, lipofection). Reaction and purification techniques can be performed, for example, using a manufacturer's specification kit or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may generally be performed in a conventional manner and as described in various general and more specific citations cited and discussed throughout this specification.

  The methods and compositions described herein are not limited to the particular methods, protocols, cell lines, components, and reagents described herein and may vary accordingly. Also, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the methods, compounds, and compositions described herein. Please understand that it is not.

As used herein, C ₁ -C _x is C ₁ -C ₂ , C ₁ -C ₃ . . . Including C ₁ -C _x. C ₁ -C _x refers to the number of carbon atoms that make up the moiety it designates (excluding optional substituents).

  An “alkyl” group refers to an aliphatic hydrocarbon group. Alkyl groups may or may not contain unsaturated units. The alkyl moiety may be a “saturated alkyl” group, which means that it contains no unsaturated units (ie, carbon-carbon double bonds or carbon-carbon triple bonds). An alkyl group also includes an “unsaturated alkyl” moiety, which means that it includes at least one unit of unsaturation. The alkyl moiety, whether saturated or unsaturated, can be branched, straight chain, or cyclic.

An “alkyl” group can have 1 to 12 carbon atoms (in any case where a numerical range such as “1-6” refers to each integer in the specified range; “1-6 carbon atoms” means that the alkyl group may consist of one carbon atom, two carbon atoms, three carbon atoms, and those containing up to six carbon atoms, This definition also includes the occurrence of the term “alkyl” for which no range of numbers is specified). The alkyl group of the compounds described herein may be designated as “C ₁ -C ₆ alkyl” or similar names. By way of example only, “C ₁ -C ₆ alkyl” indicates that there are 1 to 6 carbon atoms in the alkyl chain, ie the alkyl chain is methyl, ethyl, n-propyl, iso-propyl, n-butyl. , Iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl Selected from the group consisting of Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (ie, an arylene group).

  An “alkoxy” group refers to an “—O-alkyl” group, where alkyl is as defined herein.

The term “alkenyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with the atoms _{-C (R) = CR 2,} R refers to the remaining portion of a alkenyl group if same as or different. Non-limiting examples of an alkenyl _{group, -CH = CH 2, -C (} CH 3) = CH 2, -CH = CHCH 3, -CH = C (CH 3) 2, and _C (CH ₃₎ = CHCH 3 Including. An alkenyl moiety can be branched, straight chain, or cyclic (also known as a “cycloalkenyl” group). Alkenyl groups may have 2 to 6 carbons. An alkenyl group may be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (ie, an alkenylene group).

The term “alkynyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atom —C≡C—R, where R refers to the remainder of the alkynyl group. Non-limiting examples of alkynyl groups include —C≡CH, —C≡CCH ₃ , —C≡CCH ₂ CH ₃ , and C≡CCH ₂ CH ₂ CH ₃ . The “R” portion of the alkynyl moiety can be branched, straight chain, or cyclic. Alkynyl groups may have 2 to 6 carbons. Alkynyl groups may be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (ie, an alkynylene group).

  “Amino” refers to the group —NH 2.

The term “alkylamine” or “alkylamino” refers to a —N (alkyl) _x H _y group, where alkyl is as defined herein, and x and y are groups x = 1, y = 1, x = 2, and y = 0. When x = 2, the alkyl group combined with the nitrogen to be bonded can optionally form a cyclic ring system. “Dialkylamino” refers to the group —N (alkyl) 2, where alkyl is as defined herein.

  The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n + 2π electrons, where n is an integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (eg, phenyl, naphthalenyl) and heteroaryl groups (eg, pyridinyl, quinolinyl).

  As used herein, the term “aryl” refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be formed by 5, 6, 7, 8, 9, or more than 9 carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (ie, an arylene group).

  The term “cyclic carbon” refers to a ring in which each of the atoms forming the ring is a carbon atom. The cyclic carbon may be aryl or cycloalkyl.

“Carboxy” refers to —CO ₂ H. In some embodiments, the carboxylic acid moiety may be replaced with a “carboxylic acid bioisostere”, which is a functional group or a functional group that exhibits similar physical and / or chemical properties as the carboxylic acid moiety. Represents a part. Carboxylic acid bioisosteres have biological properties similar to carboxylic acid groups. Compounds with carboxylic acid moieties can have carboxylic acid moieties exchanged with carboxylic acid bioisosteres and have similar physical and / or biological properties when compared to carboxylic acid-containing compounds. it can. For example, in one embodiment, the carboxylic acid bioisostere ionizes as carboxylic acid groups to about the same range at physiological pH. Examples of carboxylic acid bioisosteres include, but are not limited to:

  The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (ie, the skeletal atom) is a carbon atom. Cycloalkyls can be saturated or partially unsaturated. Cycloalkyls may be fused to an aromatic ring (in which case the cycloalkyl is attached via a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

  The term “heteroaryl”, or alternatively, “heteroaromatic” refers to an aryl group containing one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the ring's backbone atoms is a nitrogen atom. Polycyclic heteroaryl groups may or may not be fused. Illustrative heteroaryl groups include the following moieties:

  A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal cyclic atom is selected from nitrogen, oxygen, and sulfur. The radical may be fused with aryl or heteroaryl. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:

The term heteroalicyclic includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyl has 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is the atoms (including heteroatoms) that make up the heterocycloalkyl (ie, the backbone atoms of the heterocycloalkyl ring). It is understood that it is not the same as the total number of.

  The term “heterocycle” refers to a ring in which at least one skeletal ring atom is selected from nitrogen, oxygen, and sulfur. The heterocycle may be heteroaryl or heterocycloalkyl.

  The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo, and iodo.

The term “haloalkyl” refers to an alkyl group substituted with one or more halogens. The halogens may be the same or different. Non-limiting examples of haloalkyl _{include -CH 2 Cl, -CF 3, -CHF} 2, -CH 2 CF 3, -CF 2 CF 3, and -CF _{(CH 3)} 3.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups that are substituted with one or more fluorine atoms, respectively. Non-limiting examples of fluoroalkyl _{include -CF 3, -CHF 2, -CH 2} F, -CH 2 CF 3, -CF 2 CF 3, -CF2CF 2 CF 3, and -CF _{(CH 3)} 3. Non-limiting examples of fluoroalkoxy _{groups, -OCF 3, -OCHF 2, -OCH} 2 F, -OCH 2 CF 3, -OCF 2 CF 3, -OCF 2 CF 2 CF 3, -OCF (CH 3) 2 , etc. including.

The term “heteroalkyl” refers to an alkyl radical in which one or more backbone chain atoms are selected from atoms other than carbon (eg, oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof). The heteroatom (s) may be placed at any internal position of the heteroalkyl group. As an _{example, -CH 2 -O-CH 3,} -CH 2 -CH 2 -O-CH 3, -CH 2 -NH-CH 3, -CH 2 -CH 2 -NH-CH 3, -CH 2 -N (CH ₃ ) —CH ₃ , —CH ₂ —CH ₂ —NH—CH ₃ , —CH ₂ —CH ₂ —N (CH ₃ ) —CH ₃ , —CH ₂ —S—CH ₂ —CH ₃ , —CH _{2 -CH 2, -S (O)} -CH 3, -CH 2 -CH 2 -S (O) 2 -CH 3, -CH 2 -NH-OCH 3, -CH 2 -O-Si (CH 3) ₃ , —CH ₂ —CH═N—OCH ₃ , and CH═CH—N (CH ₃ ) —CH ₃ . In addition, up to two heteroatoms may be consecutive, such as, for example, —CH ₂ —NH—OCH ₃ and CH ₂ —O—Si (CH ₃ ) ₃ . Except for the number of heteroatoms, “heteroalkyl” may have from 1 to 6 carbon atoms.

  The terms “single bond” or “single bond” are used when an atom connected by a single bond is considered to be part of a larger substructure, between two atoms or two parts. Refers to a chemical bond.

  The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized as chemical entities embedded in or attached to a molecule.

  As used herein, the substituent “R”, which appears alone and without a number designation, is alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon). And a substituent selected from among heterocycloalkyl.

The term “optionally substituted” or “substituted” means that the group referred to is alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide. , Aryl sulfoxide, alkyl sulfone, aryl sulfone, —CN, alkyne, C ₁ -C ₆ alkyl alkyne, halo, acyl, acyloxy, —CO ₂ H, —CO ₂ -alkyl, nitro, haloalkyl, fluoroalkyl, and amino ( One or more additional, individually and independently selected from mono- and di-substituted amino groups (eg —NH ₂ , —NHR, —N (R) ₂ )) and their protected derivatives It can be substituted with a group. As an example, the optional substituent is L _s R _s , where each L _s is independently a single bond, —O—, —C (═O) —, —S—, —S (O). _{-, - S (= O)} 2 -, - NH -, - NHC (O) -, - C (O) NH -, - S (= O) 2 NH -, - NHS (= O) 2 -, - OC (O) NH—, —NHC (O) O—, — (C ₁ -C ₆ alkyl)-, or (C ₂ -C ₆ alkenyl) —; and each R _s is independently H , (C ₁ -C ₆ alkyl), (C ₃ -C ₈ cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C ₁ -C ₆ heteroalkyl. Protecting groups that can form protected derivatives of the above substituents are found in information sources such as “Greene and Wuts” above.

  The methods and formulations described herein are in crystalline form (also known as polymorphs), or formula (I), (II), (IIA), (IIB), (IIC), (IID), This includes the use of pharmaceutically acceptable salts of compounds having the structure of (III), (IV), (V), or (VI), as well as active metabolites of these compounds having the same type of activity. In some situations, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds described herein. In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water and ethanol. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

  The terms “kit” and “product” are used synonymously.

  The term “subject” or “patient” includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkeys; cattle, horses, sheep, goats Domestic animals such as pigs; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

  The term “disease” or “disease” refers to a condition or health state of a patient or subject that can be treated with a compound or method provided herein. In embodiments, the disease is a disease associated with (eg, caused by) Olig2 or abnormal Olig2 activity (eg, brain cancer, glioblastoma multiforme, medulloblastoma, astrocytoma) , Brainstem glioma, meningioma, oligodendroglioma, melanoma, lung cancer, breast cancer, leukemia, or Down syndrome). Examples of diseases, disorders, or diseases include, but are not limited to, brain cancer, glioblastoma multiforme, medulloblastoma, astrocytoma, brainstem glioma, meningioma, oligodendroglioma, Melanoma, lung cancer, breast cancer, leukemia, Down's syndrome, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Creutzfeldt-Jakob disease, Gerstmann-Storo Isler-Shinker syndrome, prion disease, neurodegenerative disease, cancer, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), nerve Degeneration, Alzheimer's disease, Parkinson's disease, cognitive improvement, Cushing syndrome, Addison's disease, osteoporosis, frailty, muscle weakness, inflammatory disease, osteoarthritis, rheumatoid arthritis, Breath and rhinitis, diseases related to adrenal function, viral infection, immunodeficiency, immune regulation, autoimmune disease, allergy, wound healing, compulsive behavior, multidrug resistance, addiction, psychosis, anorexia, cachexia, posttraumatic stress disorder, surgery Subsequent fracture, medical catabolism, major psychotic depression, mild cognitive impairment, psychosis, dementia, hyperglycemia, stress disorder, psychosis treatment weight gain, delirium, cognitive impairment in depressed patients Cognitive decline in individuals with Down's syndrome and psychosis associated with interferon-alpha treatment, chronic pain, pain associated with gastroesophageal reflux disease, postpartum psychosis, postpartum depression, neurological disorders in premature infants, migraine Stroke, aneurysm, brain aneurysm, cerebral aneurysm, brain attack, cerebrovascular disorder, Blood, thrombosis, arterial embolism, bleeding, transient cerebral anemia, anemia, embolism, systemic hypoperfusion, venous thrombosis, arthritis, reperfusion injury, skin disease or disease, acne, vulgaris Acne, pore keratosis, acute promyelocytic leukemia, alopecia, rosacea acne, clown-like ichthyosis, xeroderma pigmentosum, keratosis, neuroblastoma, progressive ossification Includes sexual fibrosis, eczema, rosacea, sun damage, wrinkles, or superficial disease. In some examples, “disease” or “condition” refers to cancer. In some further examples, "cancer" is human cancer and carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, etc., solid and lymph cancer, kidney, breast, lung, bladder, colon, ovary, prostate, pancreas , Stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus, and liver cancer, including hepatocellular carcinoma, B acute lymphoblastic lymphoma, non-Hodgkin lymphoma (eg, Burkitt, small cell type) , And large cell lymphoma), Hodgkin lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.

  As used herein, the term “cancer” refers to all types of cancers, neoplasms, or malignant tumors found in mammals, including leukemias, carcinomas and sarcomas. Exemplary cancers that can be treated by the compounds or methods provided herein are thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma , Mesothelioma, ovary, sarcoma, stomach, uterus, or medulloblastoma cancer. Additional examples are Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary Macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, Malignant hypercalcemia, endometrial cancer, adrenocortical cancer, neoplasm of endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Or prostate cancer.

  The term “leukemia” broadly refers to progressive malignancy of hematopoietic organs, usually characterized by distorted proliferation and development of leukocytes and their precursors in blood and bone marrow. Leukemia is usually (1) duration and characteristics of acute or chronic disease; (2) the type of cells involved: spinal (myeloid), lymphoid (lymphotropic), or monocytic; and (3 ) Clinically classified based on increasing or non-increasing number of abnormal cells in leukemic, alemic (subleukemic) blood. Exemplary leukemias that can be treated by the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia Adult T-cell leukemia, non-leukemic leukemia, leukocyte leukemia, basophil leukemia, blast leukemia, bovine leukemia, chronic myeloid leukemia, skin leukemia, stem cell leukemia, eosinophilic leukemia, gross Leukemia, hair cell leukemia, hemoblastic leukemia, hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenia leukemia, lymphocytic leukemia, lymphoblastic Leukemia, lymphocytic leukemia, lymphoid leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, myelocytic giant Leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, spinal granulocytic leukemia, myelomonocytic leukemia, Negeri leukemia, plasma cell leukemia, multiple bone marrow Tumors, plasma cell leukemia, promyelocytic leukemia, leader cell leukemia, shilling leukemia, stem cell leukemia, subleukocytic leukemia, or undifferentiated cell leukemia.

  The term “sarcoma” refers to a tumor usually composed of a material such as fetal connective tissue and usually composed of strictly packaged cells embedded in a fibrillar or homogeneous material. Sarcomas that can be treated by the compounds or methods provided herein are chondrosarcoma, fibrosarcoma, lymphosarcoma, melanoma, myxosarcoma, osteosarcoma, Abemethy sarcoma, adipos sarcoma, liposarcoma , Alveolar sarcoma, enamel epithelial sarcoma, grape sarcoma, green sarcoma, choriocarcinoma, fetal sarcoma, Wilm tumor sarcoma, endometrial sarcoma, interstitial sarcoma, Ewing sarcoma, fascial sarcoma, fibroblast sarcoma , Giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B cell immunoblastosarcoma, lymphoma, T cell immunoblastosarcoma, Jensen's sarcoma , Kaposi sarcoma, Kupffer stellate cell sarcoma, angiosarcoma White blood sarcoma, malignant mesenchymal sarcoma, paraosteosarcoma, reticulosarcoma, rous sarcoma, serous cystic sarcoma, synovial sarcoma, or peripheral vasodilatory sarcoma.

  The term “melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanoma that can be treated by the compounds or methods provided herein are, for example, terminal melanoma, colorless melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passy melanoma Including melanoma, juvenile melanoma, malignant melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial enlarged melanoma.

  The term “carcinoma” refers to a malignant neoplasm composed of epithelial cells that tend to penetrate the surrounding tissue and give rise to metastases. Exemplary carcinomas that can be treated by the compounds or methods provided herein include, for example, medullary thyroid cancer, familial medullary thyroid cancer, lobular cell cancer, lobular cancer, adenococcal carcinoma, adenoid cystic cancer, Adenocarcinoma, adrenal carcinoma, bronchioloalveolar carcinoma, alveolar epithelial carcinoma, basal cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, Bronchial cancer, bronchial cancer, cerebral carcinoma, cholangiocarcinoma, choriocarcinoma, collagenous cancer, comedo cancer, endometrial cancer, phloem cancer, armored carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, gland Duct cancer, hard cancer, fetal cancer, brain-like cancer, epidermoid cancer, adenocarcinoma, adenocarcinoma, exogenous growth cancer, ulcer cancer, fiber cancer, gelatinous carcinoma (gelatini carcinoma), collagenous cancer, giant cell carcinoma, giant cell Cancer, adenocarcinoma, granulosa cell carcinoma, hair Maternal tissue cancer, hematological cancer, hepatocellular carcinoma, Hürtre cell carcinoma, hyaline carcinoma, adrenal carcinoma, childhood fetal carcinoma, carcinoma in situ, carcinoma in epidermis, carcinoma in situ, Krompecher carcinoma, Kulchtzky Cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatoid carcinoma, lymphoid epithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucous secretory carcinoma, mucinous cell carcinoma, Mucinoid epidermoid cancer, mucinous cancer, mucinous cancer, myxoma carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive cancer, spiny Cell carcinoma, soft cancer, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcoma-like cancer, Schneider carcinoma, rigid cancer, scrotal cancer, signet ring cell carcinoma, simple cancer, small cell carcinoma, potato carcinoma, spheroid cell Carcinoma, spindle cell carcinoma, spongiform carcinoma, squamous cell carcinoma (squamous) arcinoma), squamous cell carcinoma, string carcinoma, vasodilator cancer, telangiectasia, transitional cell carcinoma, nodular carcinoma, tuberculous carcinoma Or choriocarcinoma.

  A “cancer associated with abnormal Olig2 activity” (also referred to herein as “Olig2-related cancer”) is a cancer caused by abnormal Olig2 activity (eg, a mutated Olig2 gene). Olig2-related cancers are brain cancer, glioblastoma multiforme, medulloblastoma, astrocytoma, brainstem glioma, meningioma, oligodendroglioma, melanoma, lung cancer, breast cancer, It may include leukemia, T cell leukemia.

  The terms “treat”, “treating”, and “treatment” as used herein are either prophylactic and / or therapeutic, diseases Or reducing, reducing or ameliorating the symptoms of a disease, preventing further symptoms, improving or preventing the underlying cause of a symptom, inhibiting a disease or disease, eg, progression of a disease or disease Including stopping, alleviating the disease or condition, regressing the disease or condition, alleviating the condition caused by the disease or condition, or stopping the disease or condition. For example, certain methods provided herein successfully treat cancer by reducing the incidence of cancer and / or causing cancer remission. In some embodiments, certain methods provided herein reduce the incidence of Down syndrome, reduce one or more symptoms of Down syndrome, or one or more symptoms of Down syndrome. Treat Down's syndrome successfully by reducing severity.

  As used herein, amelioration of symptoms of a particular disease, disorder, or disease by administration of a particular compound or pharmaceutical composition is due to or associated with administration of the compound or composition, Refers to reducing the severity, delaying onset, slowing progression, or shortening the period, either permanent, temporary, long-term, or transient.

  The term `` modulate '' as used herein means to interact directly or indirectly with a target protein to alter the activity of the target protein, and changes in the target protein are only Examples include inhibition of target activity, or limitation or reduction of target activity.

  As used herein, the term “modulator” refers to a compound that alters the activity of a target. For example, a modulator can cause an increase or decrease in the magnitude of a particular activity of a target compared to the magnitude of activity in the absence of the modulator. In certain embodiments, the modulator is an inhibitor that reduces the magnitude of one or more activities of the target. In certain embodiments, the inhibitor completely prevents one or more activities of the target. In some embodiments, the Olig2 modulator is a compound that decreases the activity of Olig2 in a cell. In some embodiments, the Olig2 disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with Olig2 (eg, cancer or Down syndrome).

  As used herein, the term “target activity” refers to a biological activity that can be modulated by a modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and remission of one or more symptoms associated with the disease or condition. .

  With respect to Olig2 activity, the terms “inhibit”, “inhibiting”, or “inhibitor”, as used herein, refer to inhibition of oligodendrocyte transcription factor 2 activity. With respect to protein inhibitor interactions, this term refers to the activity or function of a protein relative to the activity or function of the protein (eg, Olig2 transcription factor) in the absence of the inhibitor (eg, Olig2 inhibitor or Olig2 inhibitor compound). It means negatively affecting (eg, reducing) (eg, reducing gene transcription regulated by Olig2). In some embodiments, inhibition refers to the reduction of a disease or disease symptom. In some embodiments, inhibition refers to a decrease in a signaling pathway or signaling pathway activity (eg, a decrease in a pathway for transcription regulation by Olig2 or transcription regulated by Olig2). Thus, inhibition can at least partially, partially, or completely block stimulation, reduce activation, prevent, or delay, or signal transduction, enzymatic activity, or the amount of protein (eg, Olig2) Inactivation, desensitization, or downregulation. In some embodiments, inhibition refers to inhibition of Olig2.

  As used herein, with respect to a formulation, composition, or ingredient, the term “acceptable” does not have a lasting deleterious effect on the overall health of the subject being treated. Means.

  “Pharmaceutically acceptable” as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is generally non-toxic. That is, the substance is administered to an individual without causing undesired biological effects or without adversely interacting with any of the components of the composition in which the substance is included.

  The term “pharmaceutical formulation” as used herein means a product resulting from the mixing or combination of more than one active ingredient, and includes both fixed and non-fixed formulations of the active ingredient. Including. The term “fixed formulation” refers to one active ingredient, eg, formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) Or means that both the compound of (VI) and the adjuvant are administered to the patient simultaneously in the form of a single entity or dose. The term “non-fixed formulation” refers to one active ingredient, eg, formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V ), Or (VI) and the auxiliaries are administered to the patient as separate entities at the same time, simultaneously, in succession, or without any specific time of intervention, wherein Such administration results in effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, eg the administration of 3 or more active ingredients.

  The term “pharmaceutical composition” refers to the formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V ) Or (VI) and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical composition facilitates administration of the compound to the living body. All techniques of compound administration exist in the art and include, but are not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic administration, pulmonary administration, and topical administration.

  The term “effective amount” or “therapeutically effective amount” as used herein is a sufficient amount of an agent or compound to be administered that moderates to some extent one or more symptoms of the disease or condition being treated. Represents an amount. As a result, the signs, symptoms, or causes of the disease can be reduced and / or alleviated, or any other desired modification of the biological system can be effected. For example, a therapeutically “effective amount” is a formula (I), (II), (IIA) as described herein that is required to provide a clinically significant reduction in disease symptoms. An amount of a composition comprising a compound of (IIB), (IIC), (IID), (III), (IV), (V), or (VI) is used. An appropriate “effective” amount may be determined using techniques such as dose escalation studies for any individual.

  The term “enhancement” or “enhancing” as used herein means increasing or prolonging a desired effect, either in potency or duration. . Thus, with respect to enhancing the effect of a therapeutic agent, the term “enhancing” refers to the ability to increase or prolong the effect of another therapeutic agent on the system, either in potency or duration. “An amount effective to enhance” as used herein refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

  “Contacting” is used according to its simple ordinary meaning, where at least two other species (eg, chemical compounds including biomolecules or cells) react, interact, or make physical contact. Refers to a process that allows it to be close enough to perform. However, the resulting reaction product can be generated directly from the reaction between additional reagents or from one or more intermediates of additional reagents that can be generated in the reaction mixture.

  The term “contacting” includes allowing two species to perform a reaction, interaction, or physical contact, wherein the two species are compounds as described herein. , And proteins or enzymes (eg Olig2). In some embodiments, the protein may be Olig2. In some embodiments, “contacting” includes allowing a compound described herein to interact with a protein or enzyme involved in transcription.

  The term “simultaneous administration” and the like, as used herein, is meant to encompass administration of a selected therapeutic agent to a single patient, the same or different routes of administration, or the same or different administrations. It is intended to include a treatment regimen in which the drug is administered over time.

  The term “excipient” or “carrier” as used herein refers to a relatively non-toxic chemical compound or agent that facilitates the incorporation of a compound into cells or tissues.

  The term “diluent” refers to a chemical compound that is used to dilute a compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in a buffer (which can also provide control or maintenance of pH) are utilized in the art as diluents, including but not limited to phosphate buffered saline solutions.

  A “metabolite” of a compound disclosed herein is a derivative of the compound that is formed during the metabolism of the compound. The term “active metabolite” refers to a biologically active derivative of a compound that is formed upon metabolism of the compound. The term “metabolized”, as used herein, is a process in which a particular substance is altered by an organism (including but not limited to hydrolysis reactions, reactions catalyzed by enzymes, and the like). Points to the whole. Thus, the enzyme can produce structural changes specific to the compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase is activated to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. It catalyzes the transfer of glucuronic acid molecules. Further information on metabolism may be obtained from "The Pharmaceutical Basis of Therapeutics, 9th Edition, McGraw-Hill (1996)". A metabolite of a compound disclosed herein can be obtained by administering the compound to a host and analyzing a tissue sample taken from the host, or in vitro incubation of the compound with hepatocytes and analysis of the resulting compound. It can be confirmed by either of these.

  “Bioavailability” refers to a compound disclosed herein (eg, formula (I), (II), (IIA), (IIB), (II), delivered to the systemic circulation of the animal or human being studied. IIC), (IID), (III), (IV), (V), or (VI) compound). The total drug exposure (AUC (0-∞)) when administered intravenously is usually defined as 100% organism available (F%). “Oral bioavailability” refers to the extent to which a compound disclosed herein is absorbed into the systemic circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

  “Plasma concentration” refers to the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III) disclosed herein in the plasma component of the subject's blood. , (IV), (V), or (VI) refers to the concentration of the compound. It is understood that due to variability with respect to metabolism and / or possible interactions with other therapeutic agents, plasma concentrations of the compounds disclosed herein can vary significantly from subject to subject. In accordance with one embodiment disclosed herein, plasma concentrations of the compounds disclosed herein can vary from subject to subject. Similarly, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC (0-∞)) vary from subject to subject. obtain. Due to this variability, the amount necessary to constitute a “therapeutically effective amount” of a compound may vary from subject to subject.

  As used herein, “remission” refers to amelioration of a disease or condition or at least partial alleviation of symptoms associated with the disease or condition.

  As used herein, “immune cells” include cells of the immune system and cells that perform a function or activity in the immune response, including but not limited to T cells, B cells, lymphocytes, macrophages, trees. Including dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, leukocytes, antigen-presenting cells, and natural killer cells.

<Treatment method>
In another embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI), or Or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and at least one pharmaceutically acceptable excipient.

  In another embodiment, formula (I), (II), (IIA), (IIB), (IIC), (IID), (III) for the formulation of a drug to inhibit cellular Olig2 activity , (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. Provided. The method comprises the step of treating a cell with a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI) And contacting them with the embodiments.

In a further aspect, a method of treating a disease or condition in a subject that benefits from inhibition of Olig2 activity, the method comprising the steps of formulas (I), (II), (IIA), (IIB), (IIC) , (IID), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt, solvate, or prodrug thereof The step of administering. In some embodiments, a method of treating a disease or condition in a subject that benefits from inhibition of Olig2 activity, wherein the method comprises formulas (I), (II), (IIA), (IIB), ( IIC), (IID), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt, solvate, or prodrug thereof Administering to a subject,
Here, the disease is cancer or Down's syndrome.

  In another embodiment, a method of treating a disease in a subject comprising the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), ( IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, comprising administering to a subject in need thereof: The disease is cancer or Down syndrome. In some embodiments, a method of treating cancer in a subject comprising the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III) , (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to a subject in need thereof. In some embodiments, a method of treating a subject with Down syndrome, comprising: Formula (I), (II), (IIA), (IIB), (IIC), (IID), ( III), (IV), (V), or (VI) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered to a subject in need thereof. .

  In another embodiment, a method of treating cancer in a subject comprising the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), Administering a compound of (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a subject in need thereof, wherein Cancer is brain cancer, glioblastoma multiforme, medulloblastoma, astrocytoma, brainstem glioma, meningioma, oligodendroglioma, melanoma, lung cancer, breast cancer, or leukemia is there.

  In another embodiment, a method of inhibiting the activity of Olig2 in a cell comprising the step of treating the cell with formula (I), (II), (IIA), (IIB), (IIC), (IID) , (III), (IV), (V), (VI), or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  In another aspect, in the manufacture of a medicament for the treatment of a disease, disorder, or disease that would benefit from inhibition of Olig2 activity, formula (I), (II), (IIA), (IIB), (IIC), There is the use of compounds of (IID), (III), (IV), (V), (VI), or pharmaceutically acceptable salts, solvates or prodrugs thereof.

  In one aspect, provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein and a pharmaceutically acceptable excipient. In a further aspect, a composition is provided that further comprises a second pharmaceutically active ingredient.

  In certain embodiments, provided herein is a pharmaceutical composition comprising: i) a physiologically acceptable carrier, diluent, and / or excipient; and ii) a specification herein. One or more compounds described in 1. above.

  In any of the foregoing aspects, a further embodiment comprising a single administration of an effective amount of a compound disclosed herein, further comprising: (i) Formula (I) ), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), (VI) compounds are administered once; (ii) Formula ( The compounds of I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), (VI) are (Iii) the compound is administered frequently; or (iv) the compound is administered continuously.

  In any of the foregoing embodiments, an effective amount of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or A further embodiment comprising multiple administrations of a compound of (VI), the embodiment comprising: (i) Formulas (I), (II), (IIA), (IIB), (IIC) , (IID), (III), (IV), (V), (VI) are administered in a single dose; (ii) multiple dose intervals are every 6 hours; (i) Compounds (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), (VI) are administered to mammals every 8 hours Is done. In further or alternative embodiments, the method comprises a drug holiday, wherein the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III) , (IV), (V), (VI) is temporarily stopped or administered (I), (II), (IIA), (IIB), (IIC), (II) IID), (III), (IV), (V), (VI), the dosage of the compound is temporarily reduced; at the end of the drug holiday, the formula (I), (II), (IIA), Administration of the compounds of (IIB), (IIC), (IID), (III), (IV), (V), (VI) is resumed. The length of the drug holiday can vary from 2 days to 1 year.

  In one embodiment, the compounds described herein are administered to humans. In some embodiments, the compounds described herein are administered orally.

<Examples of pharmaceutical composition and administration method>
The pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, that facilitate the processing of the active compound into a pharmaceutically usable preparation. May be. Proper formulation is dependent upon the route of administration chosen. Additional details regarding excipients suitable for the pharmaceutical compositions described herein can be found in, for example: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E. Remington's Pharmaceutical Sciences, Mack Publishing Co., Remington's Pharmaceutical Sciences. , Easton, Pennsylvania 1975; A. and Lachman, L .; Eds. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N .; Y. , 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for disclosure.

  The pharmaceutical composition, as used herein, has the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III) as described herein. , (IV), (V), (VI) and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients Refers to a mixture. The pharmaceutical composition facilitates administration of the compound to the living body. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered to a mammal having a disease, disorder, or condition to be treated. Administered in the body. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), (VI) may be used alone or as a mixture Can be used in combination with one or more therapeutic agents as a component of (as a combination therapy).

  The pharmaceutical formulations described herein include, but are not limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. It can be administered to a subject by multiple routes of administration that are not. Further, of the formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), (VI) described herein. The pharmaceutical compositions described herein comprising a compound are aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast dissolving formulations, effervescent formulations Lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsed release formulations, multiparticulate formulations, and combinations of immediate mixing and controlled release, etc. Formulated into any suitable dosage form not limited to.

  The compounds and / or compositions can be administered in a local manner (eg, frequently in a depot or sustained release formulation, via direct injection of the compound into an organ or tissue) rather than a systemic method. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In addition, drugs can be administered in targeted drug delivery systems, for example, in liposomes covered with organ-specific antibodies. Liposomes are targeted to and taken up selectively by the organ. In addition, the drug may be provided in the form of a rapid release formulation, an extended release formulation, or an intermediate release formulation.

  A pharmaceutical composition comprising a compound described herein is by way of example only, such as means of conventional mixing, dissolving, granulating, dragee manufacturing, grinding, emulsifying, encapsulating, entrapping, or compressing processes, etc. It can be manufactured in a conventional manner.

  The pharmaceutical composition may be of the formula (I), (II), (IIA), (IIB) as described herein as the active ingredient in free acid or free base form or in pharmaceutically acceptable salt form. , (IIC), (IID), (III), (IV), (V), (VI). In addition, the methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs) as well as active metabolites of these compounds having the same type of activity. In some situations, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds described herein. In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water and ethanol. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

  In certain embodiments, the compositions provided herein also include one or more preservatives to inhibit microbial activity. Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridium chloride.

  Pharmaceutical preparations for oral use comprise one or more excipients as described herein (eg, formulas (I), (II), (IIA), (IIB), (IIC), ( IID), (III), (IV), (V), (VI) compound), optionally milling the resulting mixture and, if necessary, tablets, It can be obtained by treating the mixture of granules after adding the appropriate auxiliaries to obtain pills or capsules. Suitable excipients include, for example, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, Cellulose preparations such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinyl pyrrolidone, agar, or alginic acid or a salt of alginic acid, such as sodium alginate.

  Dragee cores are provided with suitable coatings. For this purpose, concentrated molasses is used, which optionally comprises gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. May be included. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

  Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Extruded capsules can contain the active ingredients in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

  In some embodiments, the solid dosage forms disclosed herein are tablets (including suspension tablets, fast dissolving tablets, bite disintegrating tablets, rapidly disintegrating tablets, effervescent tablets, or caplets), pills, powders Agents (including sterile packaged powders, distributable powders, or foamed powders), capsules (soft capsules or hard capsules such as capsules made from animal-derived gelatin or plant-derived HPMC, or "Sprinkle capsules"), solid dispersions, solid solutions, biodegradable dosage forms, controlled release formulations, pulsed release dosage forms, multiparticulate dosage forms, pellets, granules, or aerosols. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet including but not limited to a fast dissolving tablet. In addition, pharmaceutical formulations of the compounds described herein may be administered as a single capsule or as multiple capsule dosage forms. In some embodiments, the pharmaceutical formulation is administered in 2, 3, or 4 capsules or tablets.

  In some embodiments, solid dosage forms (e.g., tablets, effervescent tablets, and capsules) are formulated according to formula (I), as described herein, to form a bulk blend composition. Mixing particles of a compound of (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI) with one or more pharmaceutical excipients To be prepared. When referring to these bulk mixed compositions as homogeneous, they are described herein so that the compositions can be subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. Particles of a compound of the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI) It means to be distributed evenly throughout. Individual unit doses can also include a film coating that disintegrates after ingestion or contact with a diluent. These formulations can be manufactured by conventional pharmacological techniques.

  The pharmaceutical solid dosage forms described herein are represented by the formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III) described herein. , (IV), (V) or (VI) and compatible carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, Lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, transdermal absorption enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or Including one or more pharmaceutically acceptable additives, such as one or more combinations thereof. In yet another aspect, standard coating procedures are used, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), and film coating is applied around the formulation of the compounds described herein. Provided. In one embodiment, some or all of the particles of the compounds described herein are coated. In yet another embodiment, some or all of the particles of the compounds described herein are microencapsulated. In yet another embodiment, particles of the compounds described herein are not microencapsulated and uncoated.

  Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy Lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, Including mannitol.

  Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrose Dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc. Including.

  As efficiently as possible, from the solid dosage form matrix, formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), Or to release the compound of (VI), disintegrants are often used in the formulation, especially when the dosage form is compressed with a binder. Disintegrants assist in rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, pregelatinized starch such as National 1551 or Amijel®, or Sodium starch glycolate, such as Promogel® or Explotab®, cellulose, eg wood products, methyl crystalline cellulose (eg Avicel®, Avicel® PH101, Avicel® PH102, Avicel (R) PH105, Elcema (R) P100, Emcocel (R), Vivacel (R), Min Tia (R), and Solka-Floc (R) )), Methylcellulose, croscarmellose, or crosslinked cellulose (such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose), crosslinked starch such as sodium starch glycolate , Cross-linked polymers such as crospovidone, cross-linked polyvinyl pyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (aluminum magnesium silicate), rubber (agar, guar, locust bean) , Karaya, pectin, or tragacanth), sodium starch glycolate, bentonite, natural sponges, surfactants, cation exchange resins and other resins, citrus pals , Sodium lauryl sulfate, sodium lauryl sulfate in combination starch, including.

  Binders provide stickiness to solid oral dosage forms: for capsule formulations filled with powder, they assist in the formation of plugs that can be filled into soft shell or hard shell capsules, and for tablet formulations They ensure that the tablets remain intact after compression and help to ensure mixing uniformity prior to the compression or filling process. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (eg, Methocel®), hydroxypropylmethylcellulose (eg, Hypermellose USP Pharmacoat) -603), hydroxypropylmethylcellulose acetate stearate (Aquate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (eg Klucel®), ethylcellulose (eg Ethocel®), and microcrystals Cellulose (for example, Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide , Bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugar (sucrose (eg Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, Xylitol (eg, Xylitab®), lactose), natural or synthetic rubber (acacia, tragacanth, gucci gum, isapol husk mucus), starch, polyvinylpyrrolidone (eg, Povidone® CL, Kollidon (R) CL, Polyplasmone (R) XL-10, and Povidone (R) K-12), larch arabinogalactan arabogalactan), Veegum (TM), polyethylene glycol, waxes, sodium alginate, including.

  Generally, a binder level of 20-70% is used for gelatin capsule formulations filled with powder. The level of binder used in tablet formulations is either direct compression, wet granulation, roller compression, or the use of other excipients such as fillers that can themselves act as moderate binders. , Different. In some embodiments, the prescriber can determine the binder level for the formulation, but up to 70% binder usage levels are common in tablet formulations.

  Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metals and alkaline earths Metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, Leucine, polyethylene glycol or methoxy polyethylene glycol (Carbowax ™, PEG4000, PEG5000, PEG6000, etc.), propylene glycol, sodium oleate, behenic acid Including seryl, palmitic acid stearic acid, glyceryl benzoate, magnesium or sodium lauryl sulfate.

  Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrose, and maltodextrin), polyols (including Mannitol, xylitol, and sorbitol), cyclodextrin and the like.

  Suitable wetting agents for use in the solid dosage forms described herein are, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monooleate Sorbitan, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (for example, Polyquat 10 (registered trademark)), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium doxate, triacetin, vitamin E TPGS and the like.

  Suitable surfactants for use in the solid dosage forms described herein are, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salt, monostearic acid Glyceryl, a copolymer of ethylene oxide and propylene oxide, such as Pluronic® (BASF).

  Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone (eg, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30), polyethylene glycol ( For example, polyethylene glycol can have a molecular weight of about 300 to 6000, about 3350 to about 4000, or about 5400 to about 7000), vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, hydroxy-propylmethylcellulose , Polysorbate 80, hydroxyethyl cellulose, sodium alginate, rubber (for example, including tragacanth gum, acacia gum, guar gum, xanthan gum) Suntan, etc.), sugar, cellulose compounds (eg, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, etc.), polysorbate-80, sodium alginate, polyoxyethylene cured sorbitan monolauric acid, polyoxyethylene cured sorbitan monolaurin Contains acids, povidone, etc.

  Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

  It should be understood that there is considerable overlap between the additives used in the solid dosage forms described herein. Thus, the above listed additives are merely exemplary and not limited to those of the types of additives that can be included in the solid dosage forms of the pharmaceutical compositions described herein. Should be done.

  In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, the plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, And castor oil.

  Compressed tablets are solid dosage forms that are prepared by compression of the above-blended bulk mix. In various embodiments, compressed tablets that are designed to dissolve in the mouth include one or more flavoring agents. In other embodiments, the compressed tablet includes a film surrounding the final compressed tablet. In some embodiments, the film coating is of the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III) as described herein from the formulation. , (IV), (V), or (VI) can provide a delayed release of the compound. In other embodiments, the film coating supports patient compliance (eg, Opadry® coating, or sugar coating). Film coatings containing Opadry® are typically in the tablet weight range from about 1% to about 3%. In other embodiments, the compressed tablets include one or more excipients.

  Capsules can be prepared, for example, by placing a bulk blend of a formulation of the above-described compound inside the capsule. In some embodiments, formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the formulation is placed in standard gelatin capsules or non-gelatin capsules, such as capsules containing HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, where the capsule can be swallowed in its entirety, or the capsule can be opened and the contents can be sprinkled on food prior to a meal. In some embodiments, the treatment dose is divided into multiple (eg, 2, 3, or 4) capsules. In some embodiments, the entire dosage of the formulation is delivered in capsule form.

  In various embodiments, the formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), Alternatively, particles of the compound of (VI) and one or more excipients are dry mixed and compressed into a mass such as a tablet, which mass is less than about 30 minutes, less than about 35 minutes, about 40 minutes after oral administration. Sufficient to provide a pharmaceutical composition that substantially disintegrates in less than minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, thereby releasing the formulation into the gastrointestinal fluid Has a good hardness.

  In another embodiment, the dosage form may comprise a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Typical materials include, but are not limited to, pH adjusters, erosion promoters, antifoaming agents, antioxidants, flavoring agents, and binders, suspending agents, disintegrants, fillers, surfactants, Includes carrier materials such as solubilizers, stabilizers, lubricants, wetting agents, and diluents.

  Materials useful for microencapsulation as described herein include compound compatible materials that sufficiently separate the compounds described herein from other incompatible excipients. Materials compatible with the compounds described herein are in vivo formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), This delays the release of the compound (V) or (VI).

  Exemplary microencapsulation materials useful for delaying release of a formulation comprising a compound described herein include, but are not limited to, hydroxypropyl cellulose ether (HPC) (Klucel® or Nissan HPC, Low substituted hydroxypropyl cellulose ether (L-HPC), etc.), hydroxypropyl methylcellulose ether (HPMC) (Sepifilm-LC, Pharmacoat®, Metallo SR, Metrocel®-E, Opadry YS, PrimaFlo, Benecel MP824 , And Benecel MP843), methylcellulose polymer (Methocel®-A, hydroxypropyl methylcellulose acetate stearate) Aquat (HF-LS, HF-LG, HF-MS), and Metalose®, etc., ethyl cellulose (EC) and mixtures thereof (E461, Ethocel®, Aqualon®-EC, Surelease) (Registered trademark), polyvinyl alcohol (PVA) (such as Opadry AMB), hydroxyethyl cellulose (such as Natrosol (registered trademark)), carboxymethyl cellulose and carboxymethyl cellulose (CMC) salts (such as Aqualon (registered trademark) -CMC), Polyvinyl alcohol, and polyethylene glycol copolymers (such as Kollicoat IR®), monoglyceride (Myverol), triglyceride (KLX), polyethylene glycol Coal, modified food starch, acrylic polymers and mixtures of acrylic polymers and cellulose ethers (Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® L100-55 Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® (Trademark) NE30D, and Eudragit (R) NE 40D), cellulose acetate phthalate, sepifils (HPMC and stearis Acid mixtures), cyclodextrins, and mixtures of these materials.

  In yet other embodiments, plasticizers such as polyethylene glycol (eg, PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800), stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. . In other embodiments, the microencapsulation material useful for delaying the release of the pharmaceutical composition is from the USP or National Pharmaceutical Collection (NF). In yet other embodiments, the microencapsulation material is Klucel. In yet other embodiments, the microencapsulation material is methocel.

  The microencapsulated compounds described herein include, for example, spray drying methods, dissolution processes on a rotating disk, hot melt processes, spray cooling methods, fluidized beds, electrostatic deposition, centrifugal discharge, rotary suspension separation, It may be formulated by methods involving polymerization at the liquid or solid gas interface, pressure venting, or spray solvent extraction tanks. In addition to these, various chemical techniques such as complex coacervation, dissolution evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, submerged drying methods, and desolvation in liquid media Can also be used. In addition, other methods such as roller compaction, discharge / spheronization, coacervation, or nanoparticle coating may also be used.

  In yet other embodiments, antifoam agents are also prepared according to the present disclosure. Effervescent salts have been used to disperse drugs in water for oral administration. The effervescent salt is a granule or coarse powder containing the drug in a dry mixture, usually composed of sodium bicarbonate, citric acid, and / or tartaric acid. When such salts are added to water, the acid and base react to liberate carbon dioxide, thereby causing “foaming”. Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate, or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. As long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or higher, any acid-base combination that results in the release of carbon dioxide is sodium bicarbonate, citric acid, and It can be used in place of the tartaric acid combination.

  In other embodiments, a formulation described herein comprising a compound described herein is a solid dispersion. The method of making such a solid dispersant is not limited, for example, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and US Patent Publication No. 2004/0013734. In yet other embodiments, the formulations described herein are solid solutions. The solid solution is further formulated by incorporating the substance with the active agent and other excipients, thereby heating the mixture, resulting in dissolution of the drug, and subsequent cooling of the resulting composition, This results in a solid mixture that can be added directly to the capsule or compressed into tablets. Methods for making such solid solutions include, but are not limited to, U.S. Pat. Nos. 4,151,273, 5,281,420, and 6,083,518.

  A solid oral dosage form of a medicament comprising a formulation described herein, including a compound described herein, has the formula (I), (II), (IIA), (IIB), (IIC) ), (IID), (III), (IV), (V), or (VI) may be further formulated to provide controlled release. Controlled release refers to the release of a compound described herein from a dosage form that is incorporated according to desired properties over an extended period of time. Controlled release characteristics include, for example, sustained release, extended release, pulsed release, and delayed release characteristics. In contrast to immediate release compositions, controlled release compositions allow for delivery of drugs to a subject over an extended period of time according to predetermined characteristics. Such a release rate provides a therapeutically effective level of drug over a long period of time, resulting in a longer pharmacological response, while side effects compared to conventional rapid release dosage forms. Minimize. Such long-term reactions provide many inherent benefits that are not achieved by corresponding short-acting, immediate-release preparations.

  In some embodiments, the solid dosage forms described herein utilize an enteric coated delayed release oral dosage form, i.e., utilizing an enteric coating to affect release in the small intestine of the gastrointestinal tract. It can be formulated as an oral dosage form of a pharmaceutical composition as described herein. Enteric-coated dosage forms contain compressed, molded, or granules of active ingredients and / or other composition ingredients, powders, pellets, beads, or particulates (which are themselves coated or uncoated) It can be an extruded tablet / mold (with or without coating). Enteric coated oral dosage forms can also be capsules (coated or uncoated) containing pellets, beads, or granules of solid carrier or composition, which are themselves coated or uncoated.

  As used herein, the term “delayed release” refers to a number of commonly predictable locations in the gastrointestinal tract that are distal to those achieved in the absence of delayed release changes. And refers to delivery such that release can be achieved. In some embodiments, the method of delayed release is a coating. The optional coating must be applied to a sufficient thickness such that the entire coating does not dissolve in gastrointestinal fluid at a pH below about 5, but dissolves at a pH above about 5. The coating may be made from:

  Acrylic polymer. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available to be solubilized in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are primarily used for colon targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach and dissolve in the intestine;

  Cellulose derivative. Examples of suitable cellulose derivatives are: ethyl cellulose; a reaction mixture of a partial acetate of cellulose and phthalic anhydride. Its performance can vary based on the degree and type of replacement. Cellulose acetate phthalate (CAP) dissolves at pH> 6. Aquateric (FMC) is an aqueous based system and is a spray dried CAP pseudolatex with <1 μm particles. Other components in Aquateric can include pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives are: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate Tossinate (eg, AQOAT (Shin Etsu)). Its performance can vary based on the degree and type of replacement. For example, HPMCP (HP-50, HP-55, HP-55S, HP-55F grade, etc.) is appropriate. Its performance can vary based on the degree and type of replacement. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF) that dissolves at pH 5, AS-MG (MF) that dissolves at pH 5.5, and higher pH AS-HG (HF). These polymers are provided as granules or fines for aqueous dispersions.

  Polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH> 5 and is not very permeable to water vapor and gastric juice.

  In some embodiments, the coating may contain and usually contain plasticizers and other possible coating excipients such as colorants, talc, and / or magnesium stearate. . Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflex A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglyceride Glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers typically contain 10-25% by weight of a plasticizer, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques such as spraying or pan coating are utilized to apply the coating. The thickness of the coating must be sufficient to ensure that the oral dosage form remains intact until the desired site of local delivery in the gastric tube is reached.

  Colorants, detackifiers, surfactants, antifoaming agents, lubricants (eg, carnuba wax or PEG) are used to solubilize or disperse coating materials, and coating performance and coated production In order to improve the product, it can be added to the coating in addition to the plasticizer.

  In other embodiments, Formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), Or a formulation described herein comprising a compound of (VI) is delivered using a pulsed dosage form. The pulse dosage form can provide one or more immediate release pulses at a predetermined time after a controlled delay time or at a specific site. Pulse dosage forms include, but are not limited to, US Patent Nos. 5,011,692; 5,017,381; 5,229,135; 5,840,329; 4,871,549; Various, including those described in 5,260,068; 5,260,069; 5,508,040; 5,567,441, and 5,837,284 It may be administered using a pulsed formulation.

  Many other types of controlled release systems are suitable for use with the formulations described herein. Examples of such delivery systems are, for example, polymer-based systems such as polylactic acid and polyglycolic acid, polyanhydrides, and polycaprolactone; sterols (cholesterol, cholesterol esters and fatty acids, or neutral fats (monoglycerides, diglycerides) Porous matrix, non-polymer based systems; hydrogel release systems; silastic systems; peptide based systems; wax coatings, biodegradable dosage forms, Includes compressed tablets using conventional binders and the like. For example, Liberman et al. , Pharmaceutical Dosage Forms, 2 Ed. , Vol. 1, pp. 209-214 (1990); Singh et al. Encyclopedia of Pharmaceutical Technology, 2nd Ed., Encyclopedia of Pharmaceutical Technology, 2nd Ed. , Pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725; 4,624,848; 4,968,509; 5,461,140; 5,456,923; No. 5,516,527; No. 5,622,721; No. 5,686,105; No. 5,700,410; No. 5,977,175; No. 6,465,014; 932, 983.

  In some embodiments, a compound described herein, eg, formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), Pharmaceutical formulations comprising particles of a compound of (V) or (VI) and at least one dispersing or suspending agent for oral administration to a subject are provided. The formulation may be a powder and / or granule for suspension, and after mixing with water, a substantially uniform suspension is obtained.

  Liquid dosage forms for oral administration were selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. It can be an aqueous suspension. For example, Singh et al. Encyclopedia of Pharmaceutical Technology, 2nd Ed., Encyclopedia of Pharmaceutical Technology, 2nd Ed. , Pp. 754-757 (2002).

  The aqueous suspensions and dispersions described herein can remain homogeneous for at least 4 hours, as defined in the USP Pharmacist Pharmacopoeia (2005 edition, Chapter 905). Homogeneity must be determined by a consistent sampling method with respect to determining the homogeneity of the overall composition. In one embodiment, the aqueous suspension can be resuspended in a homogeneous suspension by physical agitation lasting less than 1 minute. In another embodiment, the aqueous suspension can be resuspended in a homogeneous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended in a homogeneous suspension by physical agitation lasting less than 30 seconds. In yet another embodiment, agitation is not necessary to maintain a homogeneous aqueous dispersion.

  The pharmaceutical compositions described herein may include sweeteners, including but not limited to acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavaroa, berry, black currant, butterscotch, calcium citrate , Camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, syramate, dextrose, eucalyptus, Eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup, grapes, grapefruit, Honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC , Neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® powder, raspberry, root beer, lamb, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose , Sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannini Talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruity, vanilla, walnut, watermelon, red cherry, red pepper, xylitol, or any combination of these flavoring ingredients, for example Includes anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and combinations thereof .

  In some embodiments, the pharmaceutical formulations described herein can be self-emulsifying drug delivery systems (SEDDS). An emulsion is usually in the form of droplets, but in another form is a dispersion of one immiscible phase in an immiscible phase. In general, emulsions are made by vigorous mechanical dispersion. When excess water is added without any external mechanical dispersion or agitation, SEDDS spontaneously forms an emulsion, as opposed to an emulsion or microemulsion. The advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. In addition, water or an aqueous phase can be added just prior to administration to ensure the stability of the unstable or hydrophobic active ingredient. Thus, SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS may provide improved bioavailability of hydrophobic active ingredients. Methods for making self-emulsifying forms include, but are not limited to, US Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

  The aqueous dispersions described herein as given additives are often classified differently by different practitioners in the art and are commonly used for any of a variety of different functions. Or there is an overlap between the additives listed above used in the suspension. Thus, the additives listed above must be obtained as illustrative only and not as a limitation of the types of additives that can be included in the formulations described herein.

  Possible excipients for intranasal formulations include, for example, US Pat. Nos. 4,476,116, 5,116,817, and 6,391,452. Formulation solutions in saline utilize benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizers or dispersants. For example, Ansel, H .; C. et al. , Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared with suitable non-toxic pharmaceutically acceptable ingredients. The selection of an appropriate carrier will depend largely on the exact nature of the desired nasal dosage form, such as a solution, suspension, ointment, or gel. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Small amounts of other ingredients such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling or buffering agents, and other stabilizers and solubilizers may also be present. . Preferably, the nasal dosage form should be isotonic with nasal discharge.

  For administration by inhalation, the compounds described herein may be in the form of an aerosol, mist, or powder. The pharmaceutical compositions described herein can be used in pressurized packs or suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Conveniently delivered in the form of an aerosol spray provided from a nebulizer. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a measured amount. By way of example only, capsules and pills made of gelatin or the like can be formulated for use in an inhaler or infuser, including powder blends of the compounds described herein, and lactose or Contains a suitable powder base such as starch.

  Buccal formulations containing the compounds described herein include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739. , 136 may be used since various formulations are used. In addition, the buccal dosage forms described herein may further comprise a biodegradable (hydrolyzable) polymeric carrier that also functions to attach the dosage form to the buccal mucosa. The buccal dosage form is made to gradually erode over a predetermined period of time, providing compound delivery substantially entirely. Buccal drug delivery avoids the disadvantages encountered with oral drug administration, such as slow absorption, degradation of the active agent by fluid present in the gastrointestinal tract, and / or first pass inactivation in the liver. With respect to bioerodible (hydrolyzable) polymeric carriers, virtually any such carrier can be used as long as the desired drug release properties are not compromised, the carrier comprising a compound described herein, and It is to be compatible with any other component that may be present in the buccal dosage unit. In general, polymeric carriers include hydrophobic (water soluble and water swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers, and copolymers (co), such as those known as “carbomers” (Carbopol® obtained from BF Goodrich is such as One of the polymers). Other components may also be incorporated into the buccal dosage forms described herein, including, but not limited to, disintegrants, diluents, binders, lubricants, flavoring agents, coloring agents, preservatives, and the like. Including. For buccal or sublingual administration, the composition may take the form of tablets, lozenges, or gels formulated in conventional manner.

  The transdermal formulations described herein include, but are not limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, third No. 4,996,934, No. 4,031,894, No. 4,060,084, No. 4,069,307, No. 4,077,407, No. 4,201, 211, No. 4,230 105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090 No. 6,923,983, No. 6,929,801, and No. 6 It may be administered using a variety of devices including No. 946,144.

  The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients conventional in the art. In one embodiment, the transdermal formulations described herein comprise at least three components: (1) a compound formulation; (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations can include additional components such as, but not limited to, gelling agents, creams, and ointment bases. In some embodiments, the transdermal formulation may further include a woven or non-woven backing material to promote absorption and prevent removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein can remain saturated or supersaturated to promote diffusion into the skin.

  Formulations suitable for transdermal administration of the compounds described herein may utilize transdermal delivery devices and transdermal delivery patches and are dissolved and / or dispersed in a polymer or adhesive. It can be a lipophilic emulsion or a buffered aqueous solution. Such patches may be constructed for continuous delivery, pulse delivery, or on-demand delivery of pharmaceutical products. Still further, transdermal delivery of the compounds described herein can be accomplished by means such as iontophoretic patches. In addition, transdermal patches can provide controlled delivery of the compounds described herein. The absorption rate can be slowed by using a rate-controlling membrane or by trapping the compound in a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorbency. Absorption enhancers or carriers can include pharmaceutically acceptable absorbable solvents that assist passage through the skin. For example, transdermal devices include a backing material, a reservoir containing a compound optionally provided with a carrier, a rate limiting barrier for delivering the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and to the skin. In the form of a bandage, including means for securing the device.

  Formulations suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile injectable solutions or dispersions. Aseptic powders for reconstitution into can be included. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles are water, ethanol, polyol (such as propylene glycol, polyethylene glycol, glycerol, cremophor), suitable mixtures thereof, vegetable oil (olive oil) And injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying agents, and dispensing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may be desirable to include isotonic agents such as sugars and sodium chloride. Prolonged absorption of injectable pharmaceutical forms can be brought about by the use of agents that delay absorption such as aluminum monostearate and gelatin.

  For intravenous infusion, the compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. Good. For buccal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally recognized in the art. For other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the art.

  Parenteral injection may include bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage forms (eg, ampoules) or in multi-dose containers with additional preservatives. The pharmaceutical compositions described herein are in a form suitable for parenteral injection, such as a sterile suspension, solution or emulsion in an oily or aqueous vehicle, And / or formulation agents such as dispersants. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, pyrogen-free sterile water, before use.

  In certain embodiments, delivery systems for pharmaceutical compounds may be utilized, such as liposomes and emulsions. In certain embodiments, the compositions provided herein also include, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, A mucoadhesive polymer selected from sodium alginate and dextran.

  In some embodiments, the compounds described herein may be administered topically and may be a solution, suspension, lotion, gel, paste, medicated stick, balm, cream, or ointment It can be formulated into various topically administrable compositions, such as agents. Such pharmaceutical compounds can include solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

  The compounds described herein include conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone and PEG, enemas, rectal gels, rectal foams Rectal compositions such as suppositories, rectal aerosols, suppositories, jelly suppositories, or retention enemas may also be formulated. In the suppository form of the composition, a low melting wax, such as but not limited to a mixture of fatty acid glycerides, is first melted, optionally combined with cocoa butter.

  Usually, the drug, such as a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI), is a disease. Or administered in an amount effective to ameliorate the disorder or prevent progression of those symptoms (ie, a therapeutically effective amount). Thus, a therapeutically effective amount can be an amount that can at least partially prevent or reverse a disease or disorder. The dosage required to obtain an effective amount can vary depending on the drug, formulation, disease or disorder, and the individual to whom the drug is administered.

  The determination of an effective amount may also involve in vitro assays in which different amounts of drug are administered to cells in culture, and the concentration of drug effective to ameliorate some or all symptoms. Determined to calculate the required concentration in vivo. Effective amounts may also be based on in vivo animal studies.

  The agent can be administered before, simultaneously with, and after the appearance of symptoms of the disease or disorder. In some embodiments, the agent is a subject with a family history of the disease or disorder, a subject with a phenotype that can indicate an individual predisposition to the disease or disorder, or a gene that predisposes the subject to the disease or disorder. Administered to subjects with type.

<Examples of administration method and treatment regimen>
The compounds described herein can be used in the preparation of a medicament for the treatment of cancer or for the treatment of a disease or condition that would at least partially benefit from Olig2 inhibition. In addition, a method of treating any disease or condition described herein in a subject in need of such treatment is described herein in a therapeutically effective amount for said subject. Administration of a pharmaceutical composition comprising at least one compound, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

  Compositions comprising the compounds described herein can be administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially block the symptoms of the disease or condition. Effective amounts for this use depend on the severity and course of the disease or illness, previous therapy, patient health, weight and responsiveness to the drug, as well as the judgment of the treating physician.

  In prophylactic use, compositions containing the compounds described herein are administered to patients who are susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a “prophylactically effective amount or dose”. In this application, the exact amount will also depend on the health status, weight, etc. of the patient. When used in a patient, an effective amount for this use is the severity and course of the disease, disorder, or illness, previous treatment, patient health, and response to the drug, as well as the judgment of the treating physician. Depends on.

  If the patient's symptoms do not improve, after the physician's judgment, administration of the compound is routinely, i.e., long term (i.e. Over the life of the patient).

  If the patient's condition improves, administration of the compound may be given continuously after the physician's judgment; alternatively, the dose of drug administered may be temporarily reduced or temporarily It may be discontinued (ie, “drug holiday”). The length of the drug holiday is between 2 days and 1 year (just as an example, 2, 3, 4, 5, 6, 7, 10, 12, 12, 20, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days) Can do. The dose reduction during the drug holiday is about 10% to about 100% (by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% About 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% Can be included).

  Once improvement of the patient's illness occurs, a maintenance dose is administered if necessary. Subsequently, the dose and / or frequency of administration, or both, can be reduced to a level that continues to improve the disease, disorder, or condition, depending on the symptoms. However, patients require intermittent treatment on a long-term basis after any symptom recurrence.

  The amount of a given drug corresponding to such an amount depends on factors such as the particular compound, disease or condition and its severity, the identity of the subject or host in need of treatment (eg, body weight) Depending on the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated. It can be determined in a manner recognized in the field. In general, however, dosages utilized for adult human treatment typically range from about 0.02 to about 5000 mg per day, and in some embodiments about 1-1500 mg per day. is there. The desired dose may be administered in a single dose, simultaneously (or over a short period of time), or at appropriate intervals (eg, 2, 3, 4, or more sub-doses per day) May be conveniently provided in divided doses.

  The pharmaceutical compositions described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dose may be in the form of a package containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-resealable containers. Alternatively, resealable containers for multiple doses can be used, in which case it is common to include a preservative in the composition. By way of example only, formulations for parenteral injection may be provided in unit dosage forms, including but not limited to ampoules, or in multi-dose containers with additional preservatives.

  A suitable daily dose for the compounds described herein is from about 0.01 mg / kg to about 20 mg / kg. In one embodiment, the daily dose is about 0.1 mg / kg to about 10 mg / kg. Daily doses indicated in larger mammals, not limited to humans, range from about 0.5 mg to 1000 mg, single dose, divided doses including but not limited to up to 4 times daily, or extended release It is conveniently administered in the form. Unit dosage forms suitable for oral administration contain from about 1 to 500 mg of active ingredient. In one embodiment, the unit volume is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg.

  Due to the large number of things that can be changed for an individual treatment regimen, the aforementioned ranges are merely suggestive, and considerable range of motion from these recommended values is not uncommon. Such doses include, but are not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician May be changed depending on many variability.

Toxicity and therapeutic effects of such treatment regimes include, but are not limited to, determination of LD ₅₀ (50% lethal dose of the population) and ED ₅₀ (therapeutically effective dose in 50% of the population). Can be defined by standard pharmaceutical procedures in cell cultures or laboratory animals. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD ₅₀ and ED ₅₀ . Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating various ranges of dosage for use in humans. The dosage of such compounds lies preferably within a range of blood concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending on the dosage form utilized and the route of administration utilized.

<Combination treatment>
Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI), and compositions thereof are also May be used in combination with other therapeutic agents selected for therapeutic value with respect to the disease being treated. In general, in the compositions described herein, and in embodiments where combination therapy is utilized, the other agents need not be administered in the same pharmaceutical composition and have different physical and chemical properties. Must be administered by different routes. The determination of the mode of administration and the administration strategy is within the contemplation of the clinician, where possible, in the same pharmaceutical composition. Initial administration is performed according to established protocols recognized in the art and can then be modified by the clinician who has made the dose, the mode of administration, and the time of administration based on the observed effects.

  In certain instances, it may be appropriate to administer at least one compound described herein in combination with another therapeutic agent. By way of example only, such as compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI), If one of the side effects experienced by the patient after receiving one of the compounds described herein is nausea, it may be appropriate to administer the antiemetic in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administration of an adjuvant (ie, the adjuvant itself may provide a minimal therapeutic effect, Combined with another therapeutic agent, the overall therapeutic effect on the patient is enhanced). Or, by way of example only, the effect a patient may receive may be increased by administering one of the compounds described herein together with another therapeutic agent that also has a therapeutic effect (including a therapeutic regimen). Good. In all cases, regardless of the disease, disorder, or condition being treated, the overall effect a patient receives may simply be the addition of two therapeutic agents, or the patient may experience a synergistic effect.

  For therapeutic use, the compounds or drugs of the invention can be co-administered alone or in combination with conventional chemotherapy, radiation therapy, hormone therapy, and / or immunotherapy.

  As non-limiting examples, the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or Compounds of (VI) are alkylating agents (eg cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosourea, etc.), antimetabolites (eg 5-fluorouracil, azathioprine, methotrexate, Leucovorin, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, pemetrexed, raltitrexed, etc., plant alkaloids (eg vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel) Isomerase inhibitors (eg irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (eg doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, prika ), Platinum-based compounds (eg, cisplatin, oxaloplatin, carboplatin, etc.) and can be co-administered with conventional chemotherapeutic agents.

  Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI) described herein Can also be co-administered with conventional hormonal therapeutics including, but not limited to, steroids (eg, dexamethasone), finasteride, aromatase inhibitors, tamoxifen, and gonadotropin releasing hormone agonists (GnRH) such as goserelin.

In addition, the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), or (VI) described herein. ) Compounds include immunostimulants (eg, Bacillus Calmette-Guerin (BCG), levamisole, interleukin 2, alpha-interferon, etc.), monoclonal antibodies (eg, anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, And anti-VEGF monoclonal antibodies), immunotoxins (eg, anti-CD33 monoclonal antibodies-calicheamicin conjugates, anti-CD22 monoclonal antibodies-Pseudomonas aeruginosa exotoxin conjugates), and radioimmunotherapy (eg, ¹¹¹ In, ⁹⁰ Y, or ^{131 I} including anti-CD20 monoclonal antibody) which is coupled to such as, but not limited to, conventional It may be co-administered with disease therapeutic agent.

  In further embodiments, formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V), Alternatively, the compound of (VI) can also be co-administered with a STAT 3 inhibitor or a Janus kinase inhibitor.

  The particular choice of compound used will depend on the diagnosis of the attending physician and their judgment regarding the patient's condition and the appropriate treatment protocol. The compounds may be combined (eg, simultaneously, nearly simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder, or disease, the patient's condition, and the actual choice of compound used. May be administered. The determination of the order of administration of each therapeutic agent during the treatment protocol, and the number of repetitions of administration, is well within the physician's contemplation after assessment of the disease being treated and assessment of the patient's condition.

  When the drug is used in combination therapy, the therapeutically effective dose varies. Methods are described herein to experimentally determine therapeutically effective amounts of drugs and other agents used in a combination treatment regimen. For example, the use of regular dosing, ie providing more frequent and smaller doses to minimize toxic side effects has been extensively described in the literature. Combination treatment further includes periodic treatments that start and end at various times to assist in the clinical management of the patient.

  For the combination therapy described herein, the dose of the co-administered compound will of course depend on the type of co-drug utilized, the particular drug utilized, or the disease or condition being treated, etc. Depends on and fluctuates. In addition, when co-administered with one or more biologically active agents, the compounds provided herein may be administered simultaneously or sequentially with the biologically active agent (s). . When administered sequentially, the attending physician will determine the appropriate sequence of protein to administer in combination with the biologically active agent (s).

  In any case, a plurality of therapeutic agents (one of which is represented by the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III) described herein. , (IV), (V) or (VI)) may be administered in any order or simultaneously. At the same time, multiple therapeutic agents may be provided in a single unified form or in multiple forms (by way of example only, as a single pill or two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between multiple doses may vary from more than 0 weeks to less than 4 weeks. In addition, combination methods, compositions, and formulations are not limited to the use of only two drugs; the use of multiple therapeutic combinations is also envisioned.

  It will be appreciated that a dosage regimen for treating, preventing or ameliorating a disease in need of alleviation may be modified according to various factors. These factors include the disorder or disease that the subject suffers as well as the age, weight, sex, diet, and condition of the subject. Thus, the dosing regimen actually utilized may vary widely and therefore may deviate from the dosing regime described herein.

  The medicaments making up the combination therapy disclosed herein can be a combined dosage form or can be separate dosage forms intended for approximately simultaneous administration. The medicaments that make up the combination therapy may be administered sequentially with one therapeutic compound being administered by a regimen that requires two-step administration. A two-stage dosing regimen may require continuous administration of the active agent or separate administration of the active agents. The time period between multiple administration phases may range from minutes to hours depending on the properties of each drug, such as solubility, bioavailability, plasma half-life, and fast-moving properties. Changes in the circadian cycle of the target molecule concentration may also determine the optimal dosing interval.

  In addition, the compounds described herein may also be used in combination with procedures that provide additional or synergistic effects to the patient. By way of example only, a patient is expected to obtain a therapeutic and / or prophylactic effect in the methods described herein, in which case a pharmaceutical composition of the compounds described herein, And / or combination with other therapies is combined with genetic testing to determine whether an individual is a carrier of a mutated gene known to correlate with a particular disease or condition.

  The compounds and combination therapies described herein can be administered before, during, or after the onset of the disease or condition, and the timing of administration of the composition comprising the compound can vary. Thus, for example, a compound can be used as a prophylactic and can be administered continuously to a subject prone to progression of the disease or disorder to prevent the onset of the disease or disorder. The compounds and compositions can be administered to a subject during onset of symptoms or as soon as possible after onset. Administration of the compound may be initiated within the first 48 hours of onset of symptoms, preferably within the first 48 hours of onset of symptoms, more preferably within the first 6 hours of onset of symptoms, and most preferably within 3 hours of onset of symptoms. . Initial administration can be via any route, for example, intravenous infusion, bolus infusion, infusion over about 5 minutes to about 5 hours, pills, capsules, transdermal patches, buccal delivery, etc., or combinations thereof. Can be done. The compound is preferably administered as soon as practicable after the onset of the disease or illness is detected or suspected, and during a period in which treatment of the disease is required, eg, from 1 day to about 3 months . The length of treatment can vary from subject to subject, and this length can be determined using known classification criteria. For example, the compound or formulation comprising the compound can be administered for at least 2 weeks, preferably from about 1 month to about 5 years.

<Kits / Products>
Kits and articles of manufacture are also described herein for use in the therapeutic applications described herein. Such a kit is partitioned to receive one or more containers, such as, for example, vials, tubes, etc., each of which includes one of the separate elements used in the methods described herein. , Transportation devices, packages, or containers. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container can be formed from a variety of materials such as glass or plastic.

  The articles of manufacture provided herein include packaging materials. Packaging materials used for packaging pharmaceutical products include, for example, US Pat. Nos. 5,323,907 and 5,033,252. Pharmaceutical packaging materials include blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging suitable for the selected formulation and the intended mode of administration and treatment Examples include, but are not limited to, materials. Numerous formulations of compounds and compositions provided herein are contemplated as being various treatments for any disease, disorder, or condition that would benefit from inhibition of Olig2 activity.

  For example, a container can contain one or more compounds described herein, optionally as a composition or in combination with another agent as described herein. The container optionally has a sterile access port (eg, the container can be an intravenous solution bag or vial with a stopper pierceable by a hypodermic needle). Such kits optionally include a compound with an identifying instruction, or label, or instructions for use in the methods described herein.

  The kit typically has one or more different materials (eg, optionally concentrated forms of reagents and / or equipment) that are desirable from a commercial and user standpoint for the use of the compounds described herein. One or more additional containers, each of which may be included. Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes; delivery devices, packages, containers, vials, and / or tube labels that list the contents and / or use instructions As well as package inserts with instructions for use. A set of instructions is also usually included.

  The label can be on the container or attached to the container. If the letters, numbers, or other indicia that form the label are affixed, molded, or engraved on the container itself, the label can be mounted on the container. For example, as a package insert, a label can be associated with a container if present in a receptacle or transport device that also holds the container. The label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate instructions for use of the contents, such as by the methods described herein.

  In certain embodiments, the pharmaceutical composition can be provided in a pack or dispenser device that can contain one or more unit dosage forms comprising a compound provided herein. The pack may contain a metal or plastic foil, such as, for example, a blister pack. The pack or dispenser device can be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice attached to the container in a form prescribed by a government agency that regulates the manufacture, use or sale of the pharmaceutical, which notice is for administration to humans or animals. Reflects institutional approval for the form of the drug. Such notification may be, for example, a label approved by the US Food and Drug Administration regarding prescription drugs or approved product inserts. Compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container, and labeled for treatment of the indicated disease.

  Such examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

  In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific. May or may be obtained from it.

  HPLC Method: Platform (Method 1-3): Agilent 1100 Series HPLC consisting of a pump, degasser, and UV detector and equipped with an autosampler. MS detector (APCI) PE Sciex API 150 EX. Platform (Method 4): Agilent 1290 series HPLC consisting of a binary pump, degasser, and UV detector and equipped with an autosampler. MS detector AJS-ES.

  Method 1: Column-Zorbax C18, size 4.6 mm x 7.5 cm; solvent A: 0.05% TFA in water, solvent B: 0.05% TFA in acetonitrile; flow rate-0.7 ml / min Gradient: 5% B to 100% B in 9 minutes, hold at 100% B for 4 minutes, and 100% B to 5% B in 0.5 minutes; UV detector-channel 1 = 220 nm, Channel 2 = 254 nm.

  Method 2: Column-Zorbax C18, size 4.6 mm x 7.5 cm; solvent A: 0.05% TFA in water, solvent B: 0.05% TFA in acetonitrile; flow rate-0.7 ml / min Gradient: 5% B to 100% B in 5 minutes, hold at 100% B for 2 minutes, and 100% B to 5% B in 0.5 minutes; UV detector-channel 1 = 220 nm, Channel 2 = 254 nm.

  Method 3: Column-SunFire ™ (Waters) C18, size 2.1 mm x 50 mm; solvent A: 0.05% TFA in water, solvent B: 0.05% TFA in acetonitrile; flow rate -0.8 mL / Minutes: Gradient: 10% B to 90% B in 2.4 minutes, hold at 90% B for 1.25 minutes, and 90% B to 10% B in 0.25 minutes, 1.5 minutes Hold at 10% B; UV detector—channel 1 = 220 nm, channel 2 = 254 nm.

  Method 4: Column-Zorbax Eclipse Plus C18, size 2.1 × 50 mm; solvent A: 0.10% formic acid in water, solvent B: 0.00% formic acid in acetonitrile; flow rate—0.7 ml / min; Gradient: 5% B to 95% B in 5 minutes, hold at 95% B for 2 minutes; UV detector—channel 1 = 254 nm, channel 2 = 254 nm.

Example 1: Synthesis of 2- [3- (3,4-dichlorophenyl) ureido] -6-methyl-4-pyrimidinyl} amino) methane (2)>

  Step 1: 1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1)

3,4-dichlorophenyl isocyanate (5 g, 26.6 mmol), 2-amino-4-chloro-6-methylpyrimidine (3.82 g, 26.6 mmol), 1,4-dioxane (130.0 mL), The mixture was heated to reflux for 15 hours. The mixture was cooled and MeOH (50 mL) was added. The white precipitate was collected by filtration and dried to give compound (1) (6 g, 69%). LC / MS: Rt = 3.4 min, m / z = 333.3-335.3 [MH ⁺ ].

  Step 2: 1- (N-methyl {2- [3- (3,4-dichlorophenyl) ureido] -6-methyl-2-pyrimidinyl} amino) methane (2)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (83 mg, 0.25 mmol) and dimethylamine (0.125 mL, 0.25 mmol, THF) 2M solution in), diisopropylethylamine (50 μL), and dimethylacetamide (3.0 mL)) were heated at 90-95 ° C. overnight. The mixture was cooled and MeOH (3.0 mL) was added. A white precipitate formed and was filtered to give the title compound (2) (45.0 mg, 52%). LC / MS: Rt = 2.85 min, m / z = 340.3-344.2 [MH ⁺ ].

<Example 2: Synthesis of 1- (3,4-dichlorophenyl) -3- (6-methyl-4-piperidino-2-pyrimidinyl) urea (3)>

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (83 mg, 1.25 mmol), piperidine (106 mg, 1.25 mmol), dimethylacetamide (3.0 mL) was heated at 90-95 ° C. overnight. The mixture was cooled and MeOH (3.0 mL) was added. A white precipitate formed and was filtered to give the title compound (3) (63.0 mg, 66%). LC / MS: Rt = 2.95 min, m / z = 381.9-384.3 [MH ^<+ >].

<Example 3: Synthesis of 1- (3,4-dichlorophenyl) -3- (6-methyl-4-morpholino-2-pyrimidinyl) urea (4)>

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (83 mg, 0.25 mmol), morpholine (105 mg, 1.25 mmol), dimethylacetamide (3.0 mL) was heated at 90-95 ° C. overnight. The mixture was cooled and MeOH (3.0 mL) was added. The white solid precipitate was collected by filtration and dried to give the title compound (4) (61 mg, 64%). LC / MS: Rt = 3.12 min, m / z = 382.3-384.6 [MH ⁺ ].

Example 4: Synthesis of 1- (3,4-dichlorophenyl) -3- {6-methyl-4- (4-methyl-piperazin-1-yl-) pyrimidin-2-yl} -urea (5)>

1- (2-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (83 mg, 0.27 mmol) and 1-methylpiperazine (27.0 mg, 0.25 mmol) ), Diisopropylethylamine (52 μL) and dimethylacetamide (3.0 mL) were heated at 90-95 ° C. overnight. The mixture was cooled and MeOH (3.0 mL) was added. A white precipitate formed and was filtered to give the title compound (5) (55 mg, 56%). LC / MS: Rt = 2.82 min, m / z = 397.4-399.4 [MH ⁺ ].

Example 5 Synthesis of 1- (N-methyl {2- [3- (3,4-dichlorophenyl) ureido] -6-methyl-4-pyrimidinyl} amino) -2- (methylamino) ethane (6) >

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea ((1) (166 mg, 0.5 mmol) and N, N′-dimethylethane-1,2 A mixture of diamine (450 mg, 5 mmol) and 1,4-dioxane (4.0 mL) was heated overnight at 90-95 ° C. The mixture was cooled and MeOH (5.0 mL) was added. A precipitate formed and was filtered to give the title compound (6) (140 mg, 73%) LC / MS: Rt = 2.92 min, m / z = 384.3-386.4 [MH ⁺ ].

<Example 6: Synthesis of 3- {2- [3- (3,4-dichlorophenyl) ureido] -6-methyl-pyrimidin-4-yl} -aminopropanol (7)>

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (166 mg, 0.5 mmol) and 3-aminopropanol (73.0 mg, 0.5 mmol) ) And 1,4-dioxane (4.0 mL) were heated at 90-95 ° C. overnight. The mixture was cooled and MeOH (3.0 mL) was added. A white precipitate formed and was filtered to give the title compound (7) (90 mg, 56%). LC / MS: Rt = 3.06 min, m / z = 372.2-374.5 [MH ^<+ >].

Example 7 Synthesis of 1- {2- [3- (3,4-dichlorophenyl) ureido] -6-methyl-4-pyrimidin-4-yl} -amino-3- (dimethylamino) propane (8) >

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (166 mg, 0.5 mmol) and N, N′-dimethyl-1,3-propane A mixture of amide (510 mg, 5.0 mmol) and 1,4-dioxane (4.0 mL) was heated at 90-95 ° C. overnight. The mixture was cooled and MeOH (3.0 mL) was added. A white precipitate formed and was filtered to give the title compound (8) (64 mg, 33%). LC / MS: Rt = 2.96 min, m / z = 397.2-399.4 [MH ⁺ ].

<Example 8: Synthesis of 1- (4-((2-aminopropyl) amino) -6-methylpyrimidin-2-yl) -3- (3,4-dichlorophenyl) urea (9)>

A mixture of 1- (4-chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (1.05 g, 3.2 mmol) and toluene (4.7 mL) was added. The mixture was heated to reflux with stirring. To this, 1,3-propanediamine (0.32 mL, 3.8 mmol) and triethylamine (0.66 mL, 4.7 mmol) were added to maintain reflux. After cooling the formed precipitate, it was filtered and washed with methanol and diethyl ether to give the title compound (9) (1.01 g, 83%). LC / MS: Method 4: Rt = 1.44 min, m / z = 368.1-370.1 [MH ⁺ ].

<Example 9: Synthesis of 1- {2- [3- (3,4-dichlorophenyl) ureido] -6-methyl-4-pyrimidinylamino} -2-propanol (10)>

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (0.2 g, 0.56 mmol) in 2-propanol (1.1 mL). Suspended. To this was added triethylamine (0.12 mL, 0.89 mmol) followed by 1-aminopropan-2-ol (0.06 mL, 0.70 mmol) and the mixture was heated to reflux with stirring overnight. After cooling the formed precipitate, it was filtered and washed with absolute ethanol to give the title compound (10) (6.4 mg, 3%). LC / MS: Method 4: Rt = 2.22 min, m / z = 370.1-372.1 [MH ⁺ ]).

  The following examples were prepared according to a similar procedure described for Examples 1-9:

<Example 22: (±) -2- [3- (3,4-dichlorophenyl) ureido] -6-methyl-4- (3-piperidylamino) pyrimidine hydrochloride (24)>

  Step 1: tert-butyl 2- (2- (3- (3,4-dichlorophenyl) ureido) -6-methylpyrimidin-4-ylamino) piperidine-1-carboxylate (23)

  1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (905 mg, 2.75 mmol) and 1-boc-3-amino-piperidine (901 mg, 4.5 mmol) and dimethylacetamide (9.0 mL) were heated at 85 ° C. for 5 hours. The mixture was cooled and added to water. A white solid formed which was filtered, washed with 1M HCl and EA and dried (1.03 g, 76%).

  Step 2: (±) -2- [3- (3,4-Dichlorophenyl) ureido] -6-methyl-4- (3-piperidylamino) pyrimidine hydrochloride (24)

BOC derivative (9) (741 mg, 1.5 mmol) was suspended in a 9: 1 mixture of DCM: MeOH (7.5 mL) and HCl (4 M in dioxane, 7.5 mL) was added. The reaction mixture was stirred at room temperature overnight. Volatiles were removed in vacuo to give the title compound (10) as the hydrochloride salt (500 mg). LC / MS: Rt = 3.18 min, m / z = 395.1 [MH ⁺ ].

Example 23 Synthesis of 1- (3,4-dichlorophenyl) -3- (4-methyl-6-((4- (methylamino) butyl) amino) pyrimidin-2-yl) urea (26)>

  Step 1: (4- {2- [3- (3,4-Dichloro-phenyl) -ureido] -6-methyl-pyrimidin-4-ylamino} -butyl) -methyl-carbamic acid tert-butyl ester (25)

A mixture of 1- (4-chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (1.4 g, 3.2 mmol) and toluene (6.5 mL) was added. The mixture was heated to reflux with stirring. To this was added N- (4-aminobutyl) -N-methylcarbamic acid tert-butyl ester (1.0 g, 5.2 mmol) and triethylamine (0.91 mL, 6.4 mmol) and reflux was maintained for 30 minutes. . After cooling, methanol was added to form a precipitate which was filtered and washed with diethyl ether to give the title compound (25) (2.0 g, 90%). LC / MS: Rt = 3.97 min, m / z = 497.2-499.2 [MH ⁺ ].

  Step 2: 1- (3,4-Dichlorophenyl) -3- (4-methyl-6-((4- (methylamino) butyl) amino) pyrimidin-2-yl) urea

The BOC derivative (25) (2.5 g, 4.7 mmol) was suspended in DCM (15 mL) with trifluoroacetic acid (9 mL, 118 mmol) added. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was treated with 1N NaOH solution (4.7 mL, 4.7 mmol) and the mixture was stirred for 30 minutes. The layers were separated and the organics were washed with water and brine before drying and concentrated to give the title product (26). LC / MS: Method 4: Rt = 2.31 min, m / z = 397.2-399.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Examples 22-23:

Example 27: Synthesis of (±) -2- [3- (3,4-dichlorophenyl) ureido] -4- (1-ethyl-piperidin-3-yl-amino) -6-methylpyrimidine (30)>

To a solution of 2- [3- (3,4-dichlorophenyl) ureido] -6-methyl-4- (3-piperidylamino) pyrimidine (24) (215 mg, 0.5 mmol) in DCM (2.5 mL), Acetaldehyde (141 μL, 2.5 mmol) was added followed by sodium cyanoborohydride (63 mg, 1.00 mmol). The reaction mixture was stirred for 3 h then diluted with DCM (10 mL) and washed with water, NaHCO ₃ solution, and water. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified on a silica plate (elution: DCM: MeOH: NH ₄ OH: 400: 50: 2 v / v) to give the title compound (30) (50 mg, 24%). LC / MS: Rt = 3.05 min, m / z = 423.4 [MH ⁺ ].

Example 28: (±) -1- (3,4-Dichlorophenyl) -3- [4- (1-ethyl-3-piperidylamino) -6-methyl-2-pyrimidinyl] -2-imidazolidinone ( Synthesis of 34)>

  Step 1: 3- (4-Chloro-6-methyl-2-pyrimidinyl) -1- (3,4-dichlorophenyl) 2-imidazolidinone (31)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (150 mg, 0.45 mmol) in acetone (4.5 mL) and 1,2- A mixture of dibromoethane (847 mg, 4.53 mmol) and K ₂ CO ₃ (607 mg, 4.53 mmol) was heated to reflux for 3 hours. The reaction mixture was cooled, poured into water (25.0 mL) and extracted with EA (2 × 25 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. The residue was purified by chromatography (silica column, elution 0-40% EA in hexanes, gradient) to give compound (31) (100 mg, 61.2%). LC / MS: Rt = 4.15 min, m / z = 357.2 [MH ⁺ ].

  Step 2: (±) -tert-butyl 3- (2- (3- (3,4-dichlorophenyl) -2-oxoimidazolidin-1-yl) -6-methylpyrimidin-4-ylamino) piperidine-1- Carboxylate (32)

  3- (4-Chloro-6-methyl-2-pyrimidinyl) -1- (3,4-dichlorophenyl) -2-imidazolidinone (31) (100 mg, 0.28 mmol) and 1-Boc-3-amino A mixture of piperidine (901 mg, 4.5 mmol), DIPEA (73 mg, 0.56 mmol) and DMA (3.0 mL) was heated at 85 ° C. for 5 hours. The reaction was cooled and added to water. A white solid was formed, which was filtered, washed with 0.1 M HCl and EA, and dried (100 mg) to give compound (32).

  Step 3: (±) -1- (3,4-Dichlorophenyl) -3- [6-methyl-4- (3-piperidylamino) -2-pyrimidinyl] -2-imidazolidinone (33)

  Compound (32) (100 mg, 0.192 mmol) was suspended in DCM (10.0 mL) and TFA (10.0 mL) was added. The mixture was stirred overnight at room temperature. Volatiles were removed in vacuo to give 1- (4-chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) -2-imidazolidinone (33) (100 mg) as the TFA salt. Got.

  Step 4: (±) -1- (3,4-Dichlorophenyl) -3- [4- (1-ethyl-3-piperidylamino) -6-methyl-2-pyrimidinyl] -2-imidazolidinone (34)

(±) -1- (3,4-Dichlorophenyl) -3- [6-methyl-4- (3-piperidylamino) -2-pyrimidinyl] -2-imidazolidinone (33) in DCM (2.5 mL) ) (100 mg, 0.237 mmol) was added acetaldehyde (52 mg, 1.187 mmol) followed by sodium cyanoborohydride (29 mg, 0.475 mmol). The reaction mixture was stirred for 3 hours and then diluted with DCM (10 mL). The reaction mixture was washed with water, NaHCO ₃ solution, and water. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give the crude product, which was purified on a silica plate (elution, DCM: MeOH: NH 4 OH: 400: 50: 2), The title compound (34) (15 mg, 14%) was obtained. LC / MS: Rt = 0.05 min, m / z = 450.6 [MH ⁺ ].

Example 29: Synthesis of 3- (3,4-dichlorophenyl) -1- [4- (3-hydroxypropylamino) -6-methyl-2-pyrimidinyl] -2-imidazolidinone (35)

3- (4-Chloro-6-methyl-2-pyrimidinyl) -1- (3,4-dichlorophenyl) -2-imidazolidinone (31) (50 mg, 0.14 mmol), 3-aminopropanol (16 mg, 0 .21 mmol), DIPEA (271 mg, 2.1 mmol) was taken up in DMA (3.0 mL) and heated at 80 ° C. for 12 hours. The reaction mixture was then cooled and water was added. The desired compound precipitated and crystallized using a mixture of MeOH and DCM. The resulting crystals were filtered and dried to give the title compound (35) (25 mg, 45%). LC / MS: Rt = 4.24 min, m / z = 397.3 [MH ⁺ ].

Example 30: Synthesis of 3- (3,4-dichlorophenyl) -1- {4- [3- (dimethylamino) propylamino] -6-methyl-2-pyrimidinyl-2} -imidazolidinone (36)

3- (4-Chloro-6-methyl-2-pyrimidinyl) -1- (3,4-dichlorophenyl) -2-imidazolidinone (31) (50 mg, 0.14 mmol), 3- (dimethylamino) propylamine (21 mg, 0.21 mmol), DIPEA (271 mg, 2.1 mmol) was taken up in DMA (3.0 mL) and heated at 80 ° C. for 12 hours. The reaction mixture was cooled and water was added. The desired compound precipitated and crystallized using a mixture of MeOH and DCM. The resulting crystals were filtered and dried to give the title compound (36) (25 mg, 45%). LC / MS: Rt = 4.16 min, m / z = 424.3 [MH ⁺ ].

Example 31: Synthesis of 1- (3,4-dichlorophenyl) -3- [6-methyl-4- (4-pyridyloxy) -2-pyrimidinyl] -urea (37)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (50 mg, 0.15 mmol) in 1,4-dioxane, K ₂ CO ₃ (42 0.0 mg, 0.30 mmol) and 4-hydroxypyridine (21.0 mg, 0.225 mmol) were stirred at 100 ° C. for 4 hours. The reaction mixture was cooled, diluted with water and extracted with EA (2 × 10 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (37) (28.0 mg, 48%) as a solid. LC / MS: Rt = 3.09 min, m / z = 390.4 [MH ⁺ ].

Example 32: Synthesis of 1- (3,4-dichlorophenyl) -3- [6-methyl-4- (3-pyridyloxy) -2-pyrimidinyl] -urea (38)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (50 mg, 0.15 mmol) in 1,4-dioxane, K ₂ CO ₃ (42 mg , 0.30 mmol) and 3-hydroxypyridine (21 mg, 0.225 mmol) were stirred at 100 ° C. for 4 hours. The reaction mixture was cooled, diluted with water and extracted with EA (2 × 10 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (38) (29 mg, 50%) as a solid. LC / MS: Rt = 3.26 min, m / z = 390.4 [MH ⁺ ].

Example 33: Synthesis of 2- [3- (3,4-dichlorophenyl) ureido] -6-methyl-4- (4-pyridylamino) -pyrimidine (39)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3,4-dichlorophenyl) urea (1) (50 mg, 0.15 mmol), 4-aminopyridine (21.0 mg, 0.225 mmol) , Diisopropylethylamine (52 μL, 0.30 mmol) was heated in DMA (1.5 mL) for 4 h. The reaction mixture was cooled, diluted with water and extracted with EA (2 × 10 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (39) (30 mg, 52%) as a solid. LC / MS: Rt = 0.04 min, m / z = 389.3 [MH ^<+ >].

Example 34:
Synthesis of 3- {2- [3- (p-chlorophenyl) ureido] -6-methyl-4-pyrimidinylamino} -propanol (41)

  Step 1: 1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (p-chlorophenyl) urea (40)

  A mixture of 2-amino-4-chloro-6-methylpyrimidine (72 mg, 0.5 mmol) and 4-chloro-phenyl isocyanate (115 mg, 0.75 mmol) in 1,4-dioxane (1 mL) was added at 100 ° C. For 3 hours. The mixture was concentrated in vacuo and the residue was triturated with MeOH, filtered and dried to give compound (40) (72 mg, 49%) as a white solid.

  Step 2: 3- {2- [3- (p-chlorophenyl) ureido] -6-methyl-4-pyrimidinylamino} -propanol (41)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (p-chlorophenyl) urea (40) (36 mg, 0.12 mmol) and 3-amino-1-propanol (46 mg) in DMA (1 mL). , 0.61 mmol) was heated at 100 ° C. for 3 hours. The mixture was cooled. The white precipitate was filtered and air dried to give the title compound (41) (20 mg, 49%). LC / MS: Rt = 0.30 min, m / z = 336.6 [MH ⁺ ].

Example 35: Synthesis of 3- {2- [3- (m-chlorophenyl) ureido] -6-methyl-4-pyrimidinylamino} -propanol (43)

  Step 1: 1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (m-chlorophenyl) urea (42)

  A mixture of 2-amino-4-chloro-6-methylpyrimidine (72 mg, 0.5 mmol) and 3-chloro-phenyl isocyanate (115 mg, 0.75 mmol) in 1,4-dioxane (1 mL) was added at 100 ° C. For 3 hours. The mixture was concentrated in vacuo and the residue was triturated with MeOH, filtered and dried to give compound (42) (115 mg, 88%) as a white solid.

  Step 2: 3- {2- [3- (m-chlorophenyl) ureido] -6-methyl-4-pyrimidinylamino} -propanol (43)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (m-chlorophenyl) urea (38) (58 mg, 0.22 mmol) and 3-amino-1-propanol (50 mg) in DMA (1 mL). , 0.66 mmol) was heated at 100 ° C. for 3 hours. The mixture was cooled. The white precipitate was filtered and air dried to give the title compound (43) (54 mg, 82%). LC / MS: Rt = 0.11 min, m / z = 336.6 [MH ⁺ ].

Example 36 Synthesis of 1- {2- [3- (4-chloro-phenyl) ureido] -6-methyl-4-pyrimidin-ylamino} -3- (dimethylamino) propane (44)

3- (4-Chlorophenyl) -1- (4-chloro-6-methyl-2-pyrimidinyl) urea (40) (36.0 mg, 0.121 mmol) and 3- (dimethylamino) in DMA (1.0 mL) ) -1-Propylamine (37.1 mg, 0.364 mmol) was heated at 100 ° C. for 3 h. The mixture was cooled. The white precipitate was filtered and air dried to give the title compound (44) (26 mg, 59%). LC / MS: Rt = 0.53 min, m / z = 363.4 [MH ^<+ >].

Example 37 Synthesis of 1- {2- [3- (3-chloro-phenyl) ureido] -6-methyl-4-pyrimidin-ylamino} -3- (dimethyl-amino) propane (45)

3- (3-Chloro-phenyl) -1- (4-chloro-6-methyl-2-pyrimidinyl) urea (42) (58 mg, 0.22 mmol) and 3- (dimethylamino) in DMA (1.0 mL) ) -1-Propylamine (135 mg, 0.66 mmol) was heated at 100 ° C. for 3 h. The mixture was cooled. The white precipitate was filtered and air dried to give the title compound (45) (22 mg, 31%). LC / MS: Rt = 3.84 min, m / z = 363.6 [MH ⁺ ].

Example 38: 1- (2- {3- [4-Chloro-3- (trifluoromethyl) phenyl] ureido} -6-methyl-4-pyrimidinylamino) -3- (dimethylamino) propane (47) Composition

  Step 1: 3- (4-Chloro-6-methyl-2-pyrimidinyl) -1- [4-chloro-3- (trifluoromethyl) phenyl] urea (46)

  2-Amino-4-chloro-6-methylpyrimidine (72.0 mg, 0.5 mmol) and 4-chloro- (3-trifluoromethyl) phenyl isocyanate (166) in 1,4-dioxane (1.0 mL). .2 mg, 0.75 mmol) was heated at 100 ° C. for 3 hours. The reaction mixture was cooled and the precipitated product was filtered, washed with 1,4-dioxane and dried to give compound (46) (129 mg, 70%) as a white solid.

  Step 2: 1- (2- {3- [4-Chloro-3- (trifluoromethyl) phenyl] ureido} -6-methyl-4-pyrimidinylamino) -3- (dimethylamino) propane (47)

3- (4-Chloro-6-methyl-2-pyrimidinyl) -1- [4-chloro-3- (trifluoromethyl) phenyl] urea (46) (129 mg, 0.35 mmol) in DMA (1.0 mL) ) And 3- (dimethylamino) -1-propylamine (107 mg, 1.05 mmol) were heated at 100 ° C. for 3 hours. The mixture was cooled and the white precipitate was filtered, washed with water and air dried to give the title compound (47) (128 mg, 85%). LC / MS: Rt = 0.17 min, m / z = 431.3 [MH ⁺ ].

Example 39: 1- (4-Chloro-3- (trifluoromethyl) phenyl) -3- (4-((2- (dimethylamino) ethyl) amino) -6-methylpyrimidin-2-yl) urea ( 48)

3- (4-Chloro-6-methyl-2-pyrimidinyl) -1- [4-chloro-3- (trifluoromethyl) phenyl] urea (46) (100 mg, 0.26 mmol) in 2-propanol (1 mL) ), N, N-dimethylethylene-diamine (28 mg, 0.31 mmol) and trimethylamine (39 mg, 0.39 mmol) were heated to reflux at 90 ° C. After 30 minutes, the mixture was cooled to ambient temperature and diluted with MeOH. The title compound (48) was filtered as a white solid (85 mg, 78%). LC / MS: Method 4: Rt = 1.96 min, m / z = 418.2-420.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Examples 38-39:

Example 53: 1- (4-Chloro-3- (trifluoromethyl) phenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea ( 63)

  Step 1: tert-butyl (2-((2- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) -6-methylpyrimidin-4-yl) amino) ethyl) (methyl) carbamine Acid salt (62)

3- (4-Chloro-6-methyl-2-pyrimidinyl) -1- [4-chloro-3- (trifluoromethyl) phenyl] urea (46) (100 mg, 0.26 mmol), N- (2-amino A mixture of ethyl) -N-methylcarbamic acid tert-butyl ester (56 mg, 0.31 mmol) and triethylamine (40 mg, 0.39 mmol) was heated to reflux with stirring in 2-propanol (1 mL) for 30 min. . After cooling, methanol was added and the formed precipitate was filtered to give the title compound (62) (97 mg, 70%). LC / MS: Rt = 3.11 min, m / z = 504.2-506.2 [MH ⁺ ].

  Step 2: 1- (4-Chloro-3- (trifluoromethyl) phenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea (63 )

The BOC derivative (62) (97 mg, 0.18 mmol) was suspended in DCM (1.8 mL) and to this was added trifluoroacetic acid (0.15 mL, 1.8 mmol). The reaction mixture was stirred for 3 hours before adding more trifluoroacetic acid (0.15 mL). The mixture was warmed to 45 ° C. and stirred overnight. The solvent was removed under reduced pressure to give a yellow gel, which was mixed with a saturated NaHCO ₃ solution. No precipitate was observed and therefore the solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (gradient elution, 0-20% 3M NH ₃ in MeOH over CH ₂ Cl ₂ ). Purification gave the desired compound as a white solid (63) (51 mg, 66%). LC / MS: Method 4: Rt = 1.80 min, m / z = 404.2-406.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 53:

Example 58 Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3-phenylurea (69)

  Step 1: 1- (4-Chloro-6-methyl-2-pyrimidinyl) -3-phenylurea (68)

  A mixture of 2-amino-4-chloro-6-methylpyrimidine (72.0 mg, 0.5 mmol) and phenyl isocyanate (90.0 mg, 0.75 mmol) in 1,4-dioxane (1.00 mL) , And heated for 3 hours at 100 ° C. The volatiles were removed in vacuo and the residue was triturated with MeOH, filtered and dried to give compound (68) (78.0 mg, 58%) as a white solid. Got.

  Step 2: 1- (4-((3- (Dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3-phenylurea (69)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3-phenylurea (68) (37.0 mg, 0.143 mmol), and 3- (dimethylamino) -1 in DMA (1.0 mL) A mixture of -propylamine (107 mg, 1.05 mmol) was heated at 100 ° C. for 3 hours. The reaction mixture was cooled and treated with water. The white precipitate was filtered and air dried to give the title compound (69) (41 mg, 87%). LC / MS: Rt = 4.41 min, m / z = 329.4 [MH ⁺ ].

Example 59 Synthesis of 1- (4-((3-hydroxypropyl) amino) -6-methylpyrimidin-2-yl) -3-phenylurea (70)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3-phenylurea (68) (37 mg, 0.143 mmol) and 3-amino-1-propanol (54 mg, 0 in DMA (1.0 mL). .715 mmol) was heated at 100 ° C. for 3 hours. The mixture was cooled and treated with water. The white precipitate was filtered and air dried to give the title compound (70) (23 mg, 53%). LC / MS: Rt = 0.05 min, m / z = 423.1 [MH ⁺ ].

Example 60 Synthesis of 1- (4-((2-aminopropyl) amino) -6-methylpyrimidin-2-yl) -3- (3,4-dichlorophenyl) urea (71)

A mixture of 1- (4-chloro-6-methyl-2-pyrimidinyl) -3-phenylurea (68) (0.3 g, 1.1 mmol) and toluene (1.5 mL) was added to triethylamine (0.21 mL, 1 0.5 mmol) and 2-aminoethanol (0.08 mL, 1.2 mmol) and then heated to reflux with stirring. After cooling, a precipitate was formed, which was filtered and washed with methanol and diethyl ether to give the title compound (71) (0.26 g, 85%). LC / MS: Method 4: Rt = 1.75 min, m / z = 288.1 [MH ⁺ ].

Example 61 Synthesis of 1- (4-((2-aminoethyl) amino) -6-methylpyrimidin-2-yl) -3-phenylurea (72)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3-phenylurea (68) (0.2 g, 0.76 mmol) was suspended in 2-propanol (1.5 mL). To this was added triethylamine (0.15 mL, 1.1 mmol) followed by ethane-1,2-diamine (0.06 mL, 0.91 mmol) and the mixture was heated to reflux with stirring overnight. After cooling, a precipitate formed and was filtered to give the title compound (72) (0.21 g, 91%). LC / MS: Method 4: Rt = 0.86 min, m / z = 287.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Examples 58-61:

Example 70: 1- (4-Methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) -3-phenylurea (82)

  Step 1: tert-Butylmethyl (2-((6-methyl-2- (3-phenylureido) pyrimidin-4-yl) amino) ethyl) carbamate (81)

A mixture of 1- (4-chloro-6-methyl-2-pyrimidinyl) -3-phenylurea (68) (200 mg, 0.78 mmol) and toluene (1.2 mL) was added to N- (2-aminoethyl)- Treated with N-methylcarbamic acid tert-butyl ester (0.17 mL, 0.94 mmol), and triethylamine (0.16 mL, 1.2 mmol) and heated to reflux with stirring. After cooling, methanol was added and the formed precipitate was filtered and washed with diethyl ether to give the title compound (81) (212 mg, 64%). LC / MS: Method 4: Rt = 0.36 min, m / z = 401.3 [MH ⁺ ].

  Step 2: 1- (4-Methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) -3-phenylurea

The BOC derivative (81) (0.2 g, 0.5 mmol) was suspended in DCM (5 mL) and to this was added trifluoroacetic acid (0.98 mL, 12 mmol). The reaction mixture was stirred at room temperature for 15 minutes before evaporation of the solvent. The mixture was treated with DCM and 1N NaOH solution (0.5 mL, 0.5 mmol) and the mixture was stirred for 10-30 minutes. The suspension was filtered to give the title product (82) as a white solid (145 mg, 86%). LC / MS: Method 4: Rt = 0.36 min, m / z = 301.2 [MH ⁺ ].

Example 71 1- (4-Methyl-6-((3- (methylamino) propyl) amino) pyrimidin-2-yl) -3-phenylurea (83)

Example 71 was prepared from 1- (4-chloro-6-methyl-2-pyrimidinyl) -3-phenylurea (68) and N- (3-aminopropyl) -N-methylcarbamic acid tert-butyl ester. Prepared by a procedure similar to 70. (28 mg, 11%) LC / MS: Method 4: Rt = 0.38 min, m / z = 315.2 [MH ⁺ ].

Example 72 Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (trifluoromethoxy) phenyl) urea (85)

  Step 1: 1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (p-trifluoromethoxyphenyl) urea (84)

  Of 2-amino-4-chloro-6-methylpyrimidine (72.0 mg, 0.5 mmol) and 4- (trifluoromethoxy) phenyl isocyanate (152.0 mg, 0.75 mmol) in dioxane (1.00 mL). The mixture was heated at 100 ° C. for 3 hours. Volatiles were removed in vacuo and the residue was triturated with MeOH, filtered and dried to give compound (84) (120.0 mg, 69%) as a white solid.

  Step 2: 1- (4-((3- (Dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (trifluoromethoxy) phenyl) urea (85)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (p-trifluoromethoxyphenyl) urea (25) (60 mg, 0.173 mmol) and 3- (dimethyl) in DMA (1.0 mL) A mixture of amino) -1-propylamine (54 mg, 1.05 mmol) was heated at 100 ° C. for 3 hours. The reaction mixture was cooled and treated with water. The white precipitate was filtered and air dried to give the title compound (26) (41 mg, 57%). LC / MS: Rt = 0.33 min, m / z = 413.3 [MH ⁺ ].

Example 73 Synthesis of 1- (4-((3-hydroxypropyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (trifluoromethoxy) phenyl) urea (86)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (p-trifluoromethoxyphenyl) urea (84) (60 mg, 0.17 mmol) and 3-amino- in DMA (1.0 mL) A mixture of 1-propanol (65 mg, 0.86 mmol) was heated at 100 ° C. for 3 hours. The mixture was cooled. The white precipitate was filtered and air dried to give the title compound (86) (35 mg, 52%). LC / MS: Rt = 0.13 min, m / z = 386.4 [MH ⁺ ].

Example 74 Synthesis of 1- (4-((2-aminoethyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (trifluoromethoxy) phenyl) urea (87)

A mixture of 1- (4-chloro-6-methyl-2-pyrimidinyl) -3- (p-trifluoromethoxyphenyl) urea (84) (75 mg, 0.21 mmol) in 2-propanol (0.4 mL). Suspended in To this mixture was added triethylamine (0.04 mL, 0.32 mmol) followed by ethane-1,2-diamine (0.02 mL, 0.25 mmol) and the mixture was heated to reflux with stirring for several hours. . After cooling and dilution with methanol (3 mL), a precipitate formed and was filtered to give the title compound (87) (54 mg, 68%). LC / MS: Method 4: Rt = 1.50 min, m / z = 386.4 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Examples 72-74:

Example 84: Synthesis of 1- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) -3- (4- (trifluoromethoxy) phenyl) urea (98)

  Step 1: tert-Butylmethyl (2-((6-methyl-2- (3- (4- (trifluoromethoxy) phenyl) ureido) pyrimidin-4-yl) amino) ethyl) carbamate (97)

A mixture of 1- (4-chloro-6-methyl-2-pyrimidinyl) -3- (p-trifluoromethoxyphenyl) urea (84) (75 mg, 0.22 mmol) and 2-propanol (0.43 mL) Treat with N- (2-aminoethyl) -N-methylcarbamic acid tert-butyl ester (0.05 mL, 0.25 mmol), and triethylamine (0.05 mL, 0.32 mmol) and reflux with stirring for 5 hours. Until heated. After cooling, methanol (3 mL) was added and the formed precipitate was filtered to give the title compound (97) (68 mg, 65%). LC / MS: Method 4: Rt = 2.74 min, m / z = 485.3 [MH ⁺ ].

  Step 2: 1- (4-Methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) -3- (4- (trifluoromethoxy) phenyl) urea

BOC derivative (97) (75 mg, 0.16 mmol) was suspended in DCM (0.12 mL) and to this was added trifluoroacetic acid (0.12 mL, 1.6 mmol). After 5 hours at room temperature, the mixture was treated with saturated sodium bicarbonate solution until a pH of 8 was reached. The suspension so formed was filtered to give the title product (98) as a white solid (59 mg, 97%). LC / MS: Method 4: Rt = 1.50 min, m / z = 385.2 [MH ⁺ ].

Example 85: 1- [4-Methyl-6- (3-methylamino-propylamino) -pyrimidin-2-yl] -3- (4-trifluoromethoxy-phenyl) -urea (99)

Example 85 was purified except that the intermediate carbamate was first purified by preparative TLC eluting with 10% 1M NH ₄ OH in MeOH / 90% DCM (36 mg, 41%). 1- (4-chloro-6-methyl-2-pyrimidinyl) -3- (p-trifluoromethoxyphenyl) urea (84) and N- (3-aminopropyl) -N-methylcarbamic acid tert-butyl ester Prepared by a procedure analogous to Example 84. LC / MS: Method 4: Rt = 1.57 min, m / z = 400.2 [MH ⁺ ].

Example 86: 3- (dimethylamino) -1- (2- {3- [4-fluoro-3- (trifluoromethyl) phenyl] ureido} -6-methyl-4-pyrimidinylamino) propane (101) Composition

  Step 1: 1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- [4-fluoro-3- (trifluoromethyl) -phenyl] urea (100)

  2-Amino-4-chloro-6-methylpyrimidine (72 mg, 0.5 mmol) and 4-fluoro-3- (trifluoromethyl) phenyl isocyanate (154 mg, 0.75 mmol) in 1,4-dioxane (1 mL). ) Was heated at 100 ° C. for 3 hours. The reaction mixture was cooled and the precipitated product was filtered, washed with 1,4-dioxane and dried to give compound (100) (144 mg, 83%) as a white solid.

  Step 2: 3- (Dimethylamino) -1- (2- {3- [4-fluoro-3- (trifluoromethyl) phenyl] ureido} -6-methyl-4-pyrimidinylamino) propane (101)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- [4-fluoro-3- (trifluoromethyl) -phenyl] urea (100) (60 mg, 0.172 mmol) in DMA (1 mL) And a mixture of 3- (dimethylamino) -1-propylamine (53 mg, 0.516 mmol) was heated at 100 ° C. for 3 h. The mixture was cooled and treated with water. The white precipitate was filtered and air dried to give the title compound (101) (50 mg, 70%). LC / MS: Rt = 0.32 min, m / z = 415.5 [MH ⁺ ].

Example 87: 1- (4-Fluoro-3- (trifluoromethyl) phenyl) -3- (4-((3-hydroxypropyl) amino) -6-methylpyrimidin-2-yl) urea (102) Composition

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- [4-fluoro-3- (trifluoromethyl) -phenyl] urea (100) (84 mg, 0. 1 in DMA (1.0 mL). 24 mmol) and 3-amino-1-propanol (91 mg, 1.2 mmol) were heated at 100 ° C. for 3 h. The mixture was cooled and treated with water. The white precipitate was filtered and air dried to give the title compound (102) (66 mg, 71%). LC / MS: Rt = 0.21 min, m / z = 388.5 [MH ⁺ ].

Example 88 1- (4-fluoro-3- (trifluoromethyl) phenyl) -3- (4-((2- (dimethylamino) ethyl) amino) -6-methylpyrimidin-2-yl) urea ( 103)

3- (4-Fluoro-6-methyl-2-pyrimidinyl) -1- [4-chloro-3- (trifluoromethyl) phenyl] urea (100) (100 mg, 0.26 mmol) in 2-propanol (1 mL) ), N, N-dimethylethylene-diamine (0.04 mL, 0.33 mmol) and trimethylamine (0.06 mL, 0.41 mmol) were heated to reflux at 90 ° C. After 30 minutes, the mixture was cooled to ambient temperature and diluted with MeOH. The title compound (103) was filtered as a white solid (65 mg, 57%). LC / MS: Method 4: Rt = 1.57 min, m / z = 401.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Examples 86-88:

Example 104: 1- (4-fluoro-3- (trifluoromethyl) phenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea ( 120)

  Step 1: tert-butyl (2-((2- (3- (4-fluoro-3- (trifluoromethyl) phenyl) ureido) -6-methylpyrimidin-4-yl) amino) ethyl) (methyl) carbamine Acid salt (119)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- [4-fluoro-3- (trifluoromethyl) -phenyl] urea (100) (100 mg, 0.27 mmol) and 2-propanol (1 mL) ) Is treated with N- (2-aminoethyl) -N-methylcarbamic acid tert-butyl ester (0.06 mL, 0.32 mmol) and triethylamine (0.06 mL, 0.41 mmol), which is treated with 30 Heat to reflux with stirring for minutes. After cooling, ethanol was added and the formed precipitate was filtered to give the title compound (119) (116 mg, 83%). LC / MS: Method 4: Rt = 2.77 min, m / z = 487.3 [MH ⁺ ].

  Step 2: 1- (4-Fluoro-3- (trifluoromethyl) phenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea

The BOC derivative (119) (116 mg, 0.12 mmol) was suspended in DCM (1.2 mL) and to this was added trifluoroacetic acid (0.18 mL, 2.26 mmol). After 3 hours at room temperature, the mixture was warmed to 45 ° C. and stirred overnight. After cooling, the solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution. The solvent was evaporated and the resulting residue was purified by flash chromatography (gradient elution, 0-25% 3M NH ₃ in MeOH over CH ₂ Cl ₂ ) to give a white solid (120) (77 mg, 77 mg, 84%) to give the desired compound. LC / MS: Method 4: Rt = 1.38 min, m / z = 387.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 104:

Example 108 Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (4-methoxy) phenyl) urea (125)

  Step 1: 1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (4-methoxyphenyl) urea (124)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (2.6 g, 17.6 mmol) and 4-methoxyphenyl isocyanate (2.7 g, 17.6 mmol) in toluene (31 mL) was washed overnight with N Refluxed under ₂ streams. After cooling, the suspension was filtered, washed with EtOH and Et ₂ O and dried to give compound (124) (5.1 g, 65%) as a white solid. LC / MS: Method 4: Rt = 2.95 min, m / z = 293.1 [MH ⁺ ].

  Step 2: 1- (4-((3- (Dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (methoxy) phenyl) urea (125)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (p-methoxyphenyl) urea (124) (100 mg, 0.32 mmol), 3- (dimethyl) in 2-propanol (0.5 mL) A mixture of amino) -1-propylamine (0.05 mL, 0.39 mmol) and triethylamine (0.07 mL, 0.49 mmol) was heated at 80 ° C. for 2 hours. The reaction mixture was cooled and the white precipitate was filtered to give the title compound (125) (53 mg, 43%). LC / MS: Method 4: Rt = 1.02 min, m / z = 359.3 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 108:

Example 123 Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (3-methoxy) phenyl) urea (141)

  Step 1: 1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3-methoxyphenyl) urea (140)

  A mixture of 2-amino-4-chloro-6-methylpyrimidine (3 g, 20.9 mmol) and 3-methoxyphenyl isocyanate (3.4 g, 23.0 mmol) in N, N-dimethylacetamide (28 mL) was added. Heated at 100 ° C. for 80 minutes. After cooling, the mixture was diluted with MeOH (75 mL), filtered and dried to give compound (140) (3.1 g, 51%) as a white solid.

  Step 2: 1- (4-((3- (Dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (3- (methoxy) phenyl) urea (141)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3-methoxyphenyl) urea (140) (75 mg, 0.26 mmol), 2- (dimethyl) in 2-propanol (0.5 mL) Amino) -1-propylamine (0.04 mL, 0.31 mmol) and triethylamine (0.05 mL, 0.38 mmol) were heated at 80 ° C. for 23 hours. The reaction mixture was cooled and diluted with 2-propanol (3 mL). The white precipitate was filtered and washed with ethanol to give the title compound (141) (18 mg, 19%). LC / MS: Method 4: Rt = 0.32 min, m / z = 359.3 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 123:

Example 134: Synthesis of 1- (3-methoxyphenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea (153)

  Step 1: tert-Butyl (2-((2- (3- (3-methoxyphenyl) ureido) -6-methylpyrimidin-4-yl) amino) ethyl) (methyl) carbamate (152)

  A mixture of 1- (4-chloro-6-methylpyrimidin-2-yl) -3- (3-methoxyphenyl) urea (140) (75 mg, 0.26 mmol) and 2-propanol (1 mL) was added N- ( Treat with 2-aminoethyl) -N-methylcarbamic acid tert-butyl ester (0.06 mL, 0.31 mmol) and triethylamine (0.05 mL, 0.38 mmol) and heat it to reflux with stirring for 30 min. did. After cooling, methanol (5 mL) was added and the formed precipitate was filtered to give the title compound (152) (69 mg, 62%).

  Step 2: 1- (3-Methoxyphenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea

The BOC derivative (152) (69 mg, 0.16 mmol) was suspended in DCM (0.11 mL) and to this was added trifluoroacetic acid (0.12 mL, 1.5 mmol). After 2 hours at room temperature, the mixture was treated with saturated sodium bicarbonate solution. The title product was filtered as a white solid (153) (19 mg, 37%). LC / MS: Method 4: Rt = 0.95 min, m / z = 331.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 134:

Example 137: Synthesis of 1- (3-chloro-4-fluorophenyl) -3- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) urea (157)

  Step 1: 1- (3-Chloro-4-fluorophenyl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (156)

Toluene (60 mL) solution of 2-amino-4-chloro-6-methylpyrimidine (5 g, 34 mmol) and 4-methoxyphenyl isocyanate (5.9 g, 34 mmol) the mixture overnight under a stream of _{N 2} Refluxed. After cooling, the suspension was filtered, washed with MeOH and Et ₂ O and dried to give compound (156) (5.1 g, 48%) as a white solid. LC / MS: Method 4: Rt = 0.23 min, m / z = 315.0-317.1 [MH ^<+ >].

  Step 2: 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (methoxy) phenyl) urea (157)

1- (3-Chloro-4-fluorophenyl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (156) (100 mg, 0.30 mmol) in 2-propanol (0.5 mL) , 3- (dimethylamino) -1-propylamine (0.04 mL, 0.36 mmol) and triethylamine (0.06 mL, 0.45 mmol) were heated at 80 ° C. for 2 hours. The reaction mixture was cooled and the white precipitate was filtered to give the title compound (157) (83 mg, 69%). LC / MS: Method 4: Rt = 1.38 min, m / z = 382.2-384.2 [MH ^<+ >].

Example 138: Synthesis of 1- (4-((3-aminopropyl) amino) -6-methylpyrimidin-2-yl) -3- (3-chloro-4-fluorophenyl) urea (158)

1- (3-Chloro-4-fluorophenyl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (156) (148 mg, 0.45 mmol) in toluene (0.7 mL), 1 A mixture of, 3-diaminopropane (0.05 mL, 0.54 mmol) and triethylamine (0.06 mL, 0.45 mmol) was heated at reflux for 1.5 hours. The reaction mixture was cooled and the white precipitate was filtered then washed with MeOH and Et ₂ O to give the title compound (158) (83 mg, 69%). LC / MS: Method 4: Rt = 0.39 min, m / z = 353.1-356.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Examples 137-138:

Example 148: Synthesis of 1- (3-chloro-4-fluorophenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea (169)

  Step 1: tert-Butyl (2-((2- (3- (3-chloro-4-fluorophenyl) ureido) -6-methylpyrimidin-4-yl) amino) ethyl) (methyl) carbamate (168 )

A mixture of 1- (3-chloro-4-fluorophenyl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (156) (206 mg, 0.62 mmol) and toluene (2.3 mL) was added. , N- (2-aminoethyl) -N-methylcarbamic acid tert-butyl ester (0.14 mL, 0.74 mmol), and triethylamine (0.13 mL, 0.93 mmol), which was stirred for 1 hour. Heated to reflux.
After cooling, the formed precipitate was filtered and washed with MeOH and Et ₂ O to give the title compound (168) (189 mg, 64%). LC / MS: Method 4: Rt = 0.33 min, m / z = 453.2-455.2 [MH ⁺ ].

  Step 2: 1- (3-Chloro-4-fluorophenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea (169)

The BOC derivative (168) (189 mg, 0.40 mmol) was suspended in DCM (5 mL) and to this was added trifluoroacetic acid (0.77 mL, 9.9 mmol). After 15 minutes at room temperature, the solvent was evaporated and the residue was treated with DCM and 1N sodium hydroxide solution. The title product was filtered, washed with water to give a white solid (169) (117 mg, 79%) after drying. LC / MS: Method 4: Rt = 0.36 min, m / z = 353.2-355.2 [MH ⁺ ].

Example 149: Synthesis of 1- (3-chloro-4-fluorophenyl) -3- (4-methyl-6-((3- (methylamino) propyl) amino) pyrimidin-2-yl) urea (170)

Example 149 was converted to 1- (3-chloro-4-fluorophenyl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (156) and N- (3-aminopropyl) -N- Prepared in a similar manner to Example 148 from methyl carbamic acid tert-butyl ester (165 mg, 93%). LC / MS: Method 4: Rt = 0.38 min, m / z = 367.2-369.2 [MH ⁺ ].

Example 150 Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (3- (trifluoromethoxy) phenyl) urea (172)

  Step 1: 1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (3- (trifluoromethoxy) phenyl) urea (171)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (179 mg, 1.2 mmol) and 3-trifluoromethoxyphenyl isocyanate (278 mg, 1.4 mmol) in toluene (1.7 mL) was refluxed for 7 hours. I let you. After cooling, MeOH (5 mL) was added and the suspension was filtered, washed with Et ₂ O and dried to give compound (171) (66 mg, 15%) as a white solid.

  Step 2: 1- (4-((3- (Dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (3- (trifluoromethoxy) phenyl) urea (172)

1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (3- (trifluoromethoxy) phenyl) urea (171) (66 mg, 0.19 mmol) in 2-propanol (0.5 mL) , 3- (dimethylamino) -1-propylamine (0.03 mL, 0.22 mmol) and triethylamine (0.04 mL, 0.28 mmol) were heated at 80 ° C. overnight. The reaction mixture was cooled, diluted with MeOH (5 mL) and the white precipitate was filtered to give the title compound (172) (14 mg, 17%). LC / MS: Method 4: Rt = 1.65 min, m / z = 413.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 150:

Example 157: Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (3- (trifluoromethyl) phenyl) urea (180)

  Step 1: 1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (3- (trifluoromethyl) phenyl) urea (179)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (2.6 g, 17.6 mmol) and 3-trifluoromethylphenyl isocyanate (3.9 g, 17.6 mmol) in toluene (31 mL) was added. Refluxed overnight. After cooling, the suspension was filtered, washed with MeOH and Et ₂ O and dried to give compound (179) (4.4 g, 72%) as a white solid. LC / MS: Method 4: Rt = 3.65 min, m / z = 331.1 [MH ⁺ ].

  Step 2: 1- (4-((3- (Dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (3- (trifluoromethyl) phenyl) urea (180)

1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (3- (trifluoromethyl) phenyl) urea (179) (100 mg, 0.29 mmol) in 2-propanol (0.5 mL) , 3- (dimethylamino) -1-propylamine (0.04 mL, 0.34 mmol) and triethylamine (0.06 mL, 0.43 mmol) were heated at 80 ° C. for 2 hours. The reaction mixture was cooled and the white precipitate was filtered to give the title compound (180) (61 mg, 54%). LC / MS: Method 4: Rt = 1.46 min, m / z = 397.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 157:

Example 170 Synthesis of 1- (4-methyl-6-((3- (methylamino) propyl) amino) pyrimidin-2-yl) -3- (3- (trifluoromethyl) phenyl) urea (194)

  Step 1: tert-Butylmethyl (3-((6-methyl-2- (3- (3- (trifluoromethyl) phenyl) ureido) pyrimidin-4-yl) amino) propyl) carbamate (193)

A mixture of 1- (4-chloro-6-methylpyrimidin-2-yl) -3- (3- (trifluoromethyl) phenyl) urea (179) (189 mg, 0.54 mmol) and 2-propanol (5 mL) was added. , N- (3-aminopropyl) -N-methylcarbamic acid tert-butyl ester (0.13 g, 0.65 mmol), and triethylamine (0.11 mL, 0.81 mmol), which was stirred for 30 minutes. Heated to reflux. After cooling, the formed precipitate was filtered and washed with MeOH and Et ₂ O to give the title compound (193) (122 mg, 44%). LC / MS: Method 4: Rt = 2.90 min, m / z = 483.3 [MH ⁺ ].

  Step 2: 1- (4-Methyl-6-((3- (methylamino) propyl) amino) pyrimidin-2-yl) -3- (3- (trifluoromethyl) phenyl) urea

The BOC derivative (193) (122 mg, 0.24 mmol) was suspended in DCM (5 mL) and to this was added trifluoroacetic acid (0.46 mL, 6.0 mmol). After 15 minutes at room temperature, the solvent was evaporated and the residue was treated with DCM and 1N sodium hydroxide solution (0.24 mL). The title product was filtered as a white solid (194), washed with water and dried (60 mg, 62%). LC / MS: Method 4: Rt = 1.55 min, m / z = 383.2 [MH ⁺ ].

Example 171: Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (trifluoromethyl) phenyl) urea (196)

  Step 1: 1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (4- (trifluoromethyl) phenyl) urea (195)

  2-Amino-4-chloro-6-methylpyrimidine (0.82 g, 5.7 mmol) and 4-trifluoromethylphenyl isocyanate (0.91 mL, 6.5 mL) in N, N-dimethylacetamide (7.6 mL). 3 mmol) was heated at 100 ° C. for 20 minutes. After cooling, the mixture was diluted with MeOH (20 mL). The slurry was filtered, washed with MeOH and dried to give compound (195) (0.98 g, 52%) as a white solid.

  Step 2: 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (trifluoromethyl) phenyl) urea (196)

1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (4- (trifluoromethyl) phenyl) urea (195) (75 mg, 0.23 mmol) in 2-propanol (0.5 mL) , 3- (dimethylamino) -1-propylamine (0.03 mL, 0.27 mmol) and triethylamine (0.05 mL, 0.34 mmol) were heated at 80 ° C. overnight. The reaction mixture was cooled and the white precipitate was filtered to give the title compound (196) (8 mg, 8%). LC / MS: Method 4: Rt = 1.70 min, m / z = 397.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 171:

Example 183: Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (m-tolyl) urea (209)

  Step 1: 1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3-methylphenyl) urea (208)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (10 g, 68 mmol) and 3-methylphenyl isocyanate (11.1 g, 83 mmol) in N, N-dimethylacetamide (50 mL) was stirred at room temperature for 1 hour. Stir then heat at 70 ° C. for 2 hours. After cooling, the mixture was stirred overnight. The formed slurry was filtered, washed with ethanol and dried to give compound (208) (8.0 g, 43%) as a white solid. LC / MS: Method 4: Rt = 0.25 min, m / z = 277.1 [MH ⁺ ].

  Step 2: 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (m-tolyl) urea (209)

1- (4-Chloro-6-methyl-2-pyrimidinyl) -3- (3-methoxyphenyl) urea (208) (0.2 g, 0.70 mmol) in 2-propanol (1.2 mL), 3- (Dimethylamino) -1-propylamine (0.11 mL, 0.81 mmol) and triethylamine (0.15 mL, 1.1 mmol) were heated at 70 ° C. overnight. The reaction mixture was cooled and filtered. The solid was washed with ethanol to give the title compound (209) (0.19 g, 77%). LC / MS: Method 4: Rt = 0.35 min, m / z = 343.3 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 183:

Example 202: 1- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) -3- (m-tolyl) urea 1- (4-methyl-6- ( Synthesis of (2- (methylamino) ethyl) amino) pyrimidin-2-yl) -3- (m-tolyl) urea (229)

  Step 1: tert-Butylmethyl (2-((6-methyl-2- (3- (m-tolyl) ureido) pyrimidin-4-yl) amino) ethyl) carbamate (228)

A mixture of 1- (4-chloro-6-methylpyrimidin-2-yl) -3- (m-tolyl) urea (208) (200 mg, 0.70 mmol) and 2-propanol (1.2 mL) was added to N- Treat with (2-aminoethyl) -N-methylcarbamic acid tert-butyl ester (1.2 mL, 16.7 mmol) and triethylamine (0.15 mL, 1.1 mmol) until it is refluxed with stirring overnight. Heated. After cooling, the mixture was filtered and the solid was washed with ethanol to give the title compound (228) (240 mg, 83%). LC / MS: Method 4: Rt = 0.33 min, m / z = 415.3 [MH ⁺ ].

  Step 2: 1- (4-Methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) -3- (m-tolyl) urea (229)

The BOC derivative (228) (226 mg, 0.53 mmol) was suspended in DCM (0.7 mL) and to this was added trifluoroacetic acid (0.7 mL, 9 mmol). After 2 hours at room temperature, the mixture was treated with saturated sodium bicarbonate solution to achieve a pH of 8. The title product was filtered as a white solid (229) (165 mg, 100%). LC / MS: Method 4: Rt = 0.35 min, m / z = 315.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 202:

Example 206 Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (p-tolyl) urea (234)

  Step 1: 1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (p-tolyl) urea (233)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (3 g, 20 mmol) and 4-methylphenyl isocyanate (3.3 g, 25 mmol) in N, N-dimethylacetamide (15 mL) was stirred at room temperature for 1 hour. Stir then heat at 70 ° C. for 2 hours and maintain at 50 ° C. overnight. After cooling, the mixture was stirred overnight. The formed slurry was filtered, washed with ethanol and dried to give compound (233) (3.3 g, 59%) as a white solid. LC / MS: Method 4: Rt = 3.28 min, m / z = 277.1 [MH ⁺ ].

  Step 2: 1- (4-((3- (Dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (p-tolyl) urea (234)

1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (p-tolyl) urea (233) (0.2 g, 0.70 mmol) in 2-propanol (1.2 mL), 3- (Dimethylamino) -1-propylamine (0.11 mL, 0.81 mmol) and triethylamine (0.15 mL, 1.1 mmol) were heated at 70 ° C. overnight. The reaction mixture was cooled and filtered. The solid was washed with ethanol to give the title compound (234) (0.19 g, 77%). LC / MS: Method 4: Rt = 1.32 min, m / z = 343.3 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 206:

Example 219: Synthesis of 1- (4-methyl-6-((3- (methylamino) propyl) amino) pyrimidin-2-yl) -3- (p-tolyl) urea (248)

  Step 1: tert-Butylmethyl (3-((6-methyl-2- (3- (p-tolyl) ureido) pyrimidin-4-yl) amino) propyl) carbamate (247)

  A mixture of 1- (4-chloro-6-methylpyrimidin-2-yl) -3- (p-tolyl) urea (233) (200 mg, 0.70 mmol) and 2-propanol (0.96 mL) was added to N- Treat with (3-aminopropyl) -N-methylcarbamic acid tert-butyl ester (0.1 mL, 0.84 mmol) and triethylamine (0.15 mL, 1.1 mmol), which is stirred at 70 ° C. overnight. Heated. After cooling, the formed precipitate was dried to give the title compound (247) (164 mg, 53%).

  Step 2: 1- (4-Methyl-6-((3- (methylamino) propyl) amino) pyrimidin-2-yl) -3- (p-tolyl) urea (248)

BOC derivative (247) (251 mg, 0.56 mmol) was suspended in DCM (0.75 mL) and to this was added trifluoroacetic acid (0.71 mL, 9.7 mmol). After 2 hours at room temperature, the solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution to achieve a sufficient pH of 8. The title product was filtered as a white solid (248), washed with water and dried (160 mg, 82%). LC / MS: Method 4: Rt 1.22 min. m / z = 329.2 [MH ^<+ >].

Example 220 Synthesis of 1- (4-Methyl-6-((piperidin-3-ylmethyl) amino) pyrimidin-2-yl) -3- (p-tolyl) urea (249)

Example 220 was converted to 1- (4-chloro-6-methylpyrimidin-2-yl) -3- (p-tolyl) urea (233) and tert-butyl 3- (aminomethyl) piperidine-1-carboxylate (180 mg, 71%) was prepared in a similar manner to Example 219. LC / MS: Method 4: Rt = 1.31 min, m / z = 355.3 [MH ⁺ ].

Example 221: Synthesis of 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (3,4-dimethylphenyl) urea (251)

  Step 1: 1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (3,4-dimethylphenyl) urea (250)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (10 g, 68 mmol) and 3,4-dimethylphenyl isocyanate (12.3 g, 83 mmol) in N, N-dimethylacetamide (60 mL) was added for 1 hour. Stir at room temperature and then heat at 50 ° C. overnight. After cooling, the mixture was stirred overnight. The formed slurry was filtered, washed with ether and dried to give compound (250) (4.8 g, 24%) as a white solid. LC / MS: Method 4: Rt = 0.25 min, m / z = 277.1 [MH ⁺ ]. This material was used directly in the next step.

  Step 2: 1- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) -3- (3,4-dimethylphenyl) urea (251)

1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (3,4-dimethylphenyl) urea (250) (0.2 g, 0.67 mmol) in 2-propanol (1.1 mL) 3- (Dimethylamino) -1-propylamine (0.11 mL, 0.81 mmol) and triethylamine (0.14 mL, 1.0 mmol) were heated at 70 ° C. overnight. The reaction mixture was cooled and filtered. The solid was washed with ethanol to give the title compound (251) (198 mg, 83%). LC / MS: Method 4: Rt = 0.35 min, m / z = 357.3 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 221:

Example 237: Synthesis of 1- (3,4-dimethylphenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea (268)

  Step 1: tert-butyl (2-((2- (3- (3,4-dimethylphenyl) ureido) -6-methylpyrimidin-4-yl) amino) ethyl) (methyl) carbamate (267)

  A mixture of 1- (4-chloro-6-methylpyrimidin-2-yl) -3- (3,4-dimethylphenyl) urea (250) (200 mg, 0.70 mmol) and 2-propanol (1.2 mL) was added. , N- (2-aminoethyl) -N-methylcarbamic acid tert-butyl ester (1.2 mL, 16.7 mmol), and triethylamine (0.15 mL, 1.1 mmol), which was stirred overnight. Heated to reflux. After cooling, the mixture was filtered and the solid was washed with ethanol to give the title compound (267) (168 mg, 59%).

  Step 2: 1- (3,4-Dimethylphenyl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea (268)

The BOC derivative (267) (167 mg, 0.38 mmol) was suspended in DCM (0.5 mL) and to this was added trifluoroacetic acid (0.48 mL, 6 mmol). After 2 hours at room temperature, the mixture was treated with saturated sodium bicarbonate solution to achieve a pH of 8. The title product was filtered as a white solid (268) (115 mg, 93%). LC / MS: Method 4: Rt = 0.37 min, m / z = 329.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 237:

Example 241: Synthesis of N- (3-((2- (3- (3,4-dichlorophenyl) ureido) -6-methylpyrimidin-4-yl) amino) propyl) acetamide (272)

1- (4-((3-Aminopropyl) amino) -6-methylpyrimidin-2-yl) -3- (3,4-dichlorophenyl) urea (9) (100 mg, 0) in DCM (0.54 mL). .27 mmol), acetic anhydride (0.03 mL, 0.29 mmol), pyridine (0.14 mL, 1.7 mmol) and a catalytic amount of N, N-dimethylaminopyridine were stirred for 2.5 hours at room temperature. At this time, the mixture was cooled to −20 ° C. prior to dilution with MeOH (5 mL). The resulting solid was filtered and dried to give the title product (272) (75 mg, 64%). LC / MS: Method 4: Rt = 2.07 min, m / z = 411.2-413.2 [MH ⁺ ].

Example 242: Synthesis of N- (3-((6-methyl-2- (3- (4- (trifluoromethoxy) phenyl) ureido) pyrimidin-4-yl) amino) propyl) acetamide (273)

Example 242 was converted to 1- (4-((3-aminopropyl) amino) -6-methylpyrimidin-2-yl) -3- (3- (trifluoromethoxy) phenyl) urea (89) (11 mg, 20 %) From a similar procedure as described for Example 241. LC / MS: Method 4: Rt = 2.02 min, m / z = 427.2 [MH ⁺ ].

Example 243: Synthesis of N- (3-((6-methyl-2- (3- (4- (trifluoromethoxy) phenyl) ureido) pyrimidin-4-yl) amino) ethyl) acetamide (274)

Example 243 was converted to 1- (4-((3-aminoethyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (trifluoromethoxy) phenyl) urea (87) (11 mg, 20 %) From a similar procedure as described for Example 241. LC / MS: Method 4: Rt = 2.02 min, m / z = 427.2 [MH ⁺ ].

Example 244: Synthesis of N- (3-((2- (3- (4-methoxyphenyl) ureido) -6-methylpyrimidin-4-yl) amino) propyl) acetamide (275)

Example 244 was prepared from 1- (4-((3-aminopropyl) amino) -6-methylpyrimidin-2-yl) -3- (4-methoxyphenyl) urea (131) (47 mg, 56%). Prepared by a procedure analogous to that described for Example 241. LC / MS: Method 4: Rt = 1.44 min, m / z = 373.2 [MH ⁺ ].

Example 245: Synthesis of N- (2-((2- (3- (4-methoxyphenyl) ureido) -6-methylpyrimidin-4-yl) amino) ethyl) acetamide (276)

Example 245 was prepared from 1- (4-((2-aminoethyl) amino) -6-methylpyrimidin-2-yl) -3- (4-methoxyphenyl) urea (127) (19 mg, 49%). Prepared by a procedure analogous to that described for Example 241. LC / MS: Method 4: Rt = 1.37 min, m / z = 359.2 [MH ⁺ ].

Example 246: Synthesis of N- (2-((2- (3- (4-methoxyphenyl) ureido) -6-methylpyrimidin-4-yl) amino) ethyl) acetamide (277)

Example 246 was converted to 1- (4-((2-aminoethyl) amino) -6-methylpyrimidin-2-yl) -3- (3- (trifluoromethyl) phenyl) urea (182) (12 mg, 33 %) From a similar procedure as described for Example 241. LC / MS: Method 4: Rt = 1.87 min, m / z = 397.2 [MH ⁺ ].

Example 247: Synthesis of N- (3-((2- (3- (3-chloro-4-fluorophenyl) ureido) -6-methylpyrimidin-4-yl) amino) propyl) acetamide (278)

Example 247 was converted to 1- (4-((3-aminopropyl) amino) -6-methylpyrimidin-2-yl) -3- (3-chloro-4-fluorophenyl) urea (158) (24 mg, 43 %) From a similar procedure as described for Example 241. LC / MS: Method 4: Rt = 1.83 min, m / z = 395.2 [MH ⁺ ].

Example 248: N- (2-((6-Methyl-2- (3- (4- (trifluoromethoxy) phenyl) -ureido) -pyrimidin-4-yl) -ethyl) methanesulfonamide (279) Composition

1- (4-((3-Aminoethyl) amino) -6-methylpyrimidin-2-yl) -3- (4- (trifluoromethoxy) phenyl) in DCM (0.48 mL) cooled to 0 ° C. To a mixture of urea (87) (53 mg, 0.14 mmol) and triethylamine (0.04 mL, 0.28 mmol) was added methanesulfonyl chloride (0.01 mL, 0.16 mmol) and this was stirred for 5 hours at room temperature. At this time, the mixture was diluted with MeOH (5 mL) and the resulting solid was filtered. This material was purified by silica gel chromatography using a gradient of 0-10% MeOH in DCM. Evaporation of appropriate fractions gave the title product (279) (5 mg, 7%). LC / MS: Method 4: Rt = 2.14 min, m / z = 449.1 [MH ⁺ ].

Example 249: 1- (benzo [d] [1,3] dioxol-5-yl) -3- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) Synthesis of urea (281)

  Step 1: 1- (Benzo [d] [1,3] dioxol-5-yl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (280)

  2-Amino-4-chloro-6-methylpyrimidine (0.51 g, 3.5 mmol) and 2H-benzo [d] 1,3-dioxolane-5-isocyanate (0.64 g) in toluene (4.7 mL). 3.9 mmol) was heated with stirring at 100 ° C. for 2 hours and then at 50 ° C. overnight. After cooling, the mixture was diluted with methanol (10 mL) and the formed slurry was filtered, triturated with methanol and dried to give compound (280) (0.48 g, 44%). This material was used directly in the next step.

  Step 2: 1- (Benzo [d] [1,3] dioxol-5-yl) -3- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) urea (281)

1- (Benzo [d] [1,3] dioxol-5-yl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (280) in 2-propanol (0.66 mL) ( 0.1 g, 0.33 mmol), 3- (dimethylamino) -1-propylamine (0.05 mL, 0.40 mmol) and triethylamine (0.07 mL, 0.5 mmol) were heated at 80 ° C. overnight. did. The reaction mixture was cooled and filtered and the solid was purified by preparative TLC eluting with 30% 1M NH ₄ OH in MeOH / 70% DCM to give the title compound (281) (27 mg, 31% ) LC / MS: Method 4: Rt = 0.98 min, m / z = 373.2 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 249:

Example 255: 1- (Benzo [d] [1,3] dioxol-5-yl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) Synthesis of urea (288)

  Step 1: tert-Butyl (2-((2- (3- (benzo [d] [1,3] dioxol-5-yl) ureido) -6-methylpyrimidin-4-yl) amino) ethyl) (methyl ) Carbamate (287)

1- (Benzo [d] [1,3] dioxol-5-yl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (280) (82 mg, 0.27 mmol) and 2-propanol (0.5 mL) is treated with N- (2-aminoethyl) -N-methylcarbamic acid tert-butyl ester (0.06 mL, 0.32 mmol) and triethylamine (0.06 mL, 0.40 mmol)). This was heated to 80 ° C. with stirring overnight. After cooling, the reaction was diluted with MeOH (3 mL) and the formed precipitate was filtered to give the title compound (287) (85 mg, 72%). LC / MS: Method 4: Rt = 2.14 min, m / z = 445.3 [MH ⁺ ].

  Step 2: 1- (Benzo [d] [1,3] dioxol-5-yl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea

BOC derivative (287) (85 mg, 0.19 mmol) was suspended in DCM (0.15 mL), to which trifluoroacetic acid (0.14 mL, 1.9 mmol) was added. After 40 minutes at room temperature, the solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution to achieve a pH of 8. The title product was filtered and washed with water to give a white solid (288) after drying (30 mg, 46%). LC / MS: Method 4: Rt = 0.94 min, m / z = 345.2 [MH ⁺ ].

Example 256: 1- (benzo [d] [1,3] dioxol-5-yl) -3- (4-methyl-6-((3- (methylamino) propyl) amino) pyrimidin-2-yl) Synthesis of urea (289)

Example 262 was prepared from 1- (benzo [d] [1,3] dioxol-5-yl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (287) and N- (3- Prepared in a similar manner to Example 261 from (aminopropyl) -N-methylcarbamic acid tert-butyl ester (17 mg, 19%). LC / MS: Method 4: Rt = 1.01 min, m / z = 359.2 [MH ⁺ ].

Example 257: 1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -3- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidine -2-yl) urea (291) synthesis

  Step 1: 1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) urea (290)

  2-Amino-4-chloro-6-methylpyrimidine (2.1 g, 15 mmol) and 2H, 3H-benzo [e] 1,4-dioxane-6-isocyanate (3 g, 16 mmol) in toluene (19.9 mL). The mixture was heated with stirring at 100 ° C. for 1 hour and then at 50 ° C. overnight. After cooling, the mixture was diluted with methanol (20 mL) and the formed slurry was filtered, triturated with methanol and dried to give compound (290) (2.8 g, 59%). This material was used directly in the next step.

  Step 2: 1- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) -3- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidine- 2-yl) urea (291)

1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) in 2-propanol (0.47 mL) A mixture of urea (290) (75 mg, 0.23 mmol), 3- (dimethylamino) -1-propylamine (0.04 mL, 0.28 mmol) and triethylamine (0.05 mL, 0.35 mmol) was added at 80 ° C. Heated for 5 hours. The reaction mixture was cooled and filtered and the solid was purified by preparative TLC eluting with 30% 1M NH ₄ OH in MeOH / 70% DCM to give the title compound (291) (17 mg, 19% ) LC / MS: Method 4: Rt = 1.04 min, m / z = 387.3 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 257:

Example 263: 1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidine -2-yl) urea (298) synthesis

  Step 1: tert-butyl (2-((2- (3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ureido) -6-methylpyrimidin-4-yl) amino ) Ethyl) (methyl) carbamate (297)

1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) urea (290) (75 mg, 0.23 mmol) ) And 2-propanol (0.48 mL) were added N- (2-aminoethyl) -N-methylcarbamic acid tert-butyl ester (0.05 mL, 0.28 mmol) and triethylamine (0.05 mL, 0.35 mmol). And heated to 80 ° C. with stirring overnight. After cooling, the reaction was diluted with MeOH (3 mL) and the formed precipitate was filtered and further washed with MeOH to give the title compound (297) (76 mg, 70%). LC / MS: Method 4: Rt = 2.10 min, m / z = 459.3 [MH ⁺ ].

  Step 2: 1- (Benzo [d] [1,3] dioxol-5-yl) -3- (4-methyl-6-((2- (methylamino) ethyl) amino) pyrimidin-2-yl) urea

The BOC derivative (297) (76 mg, 0.16 mmol) was suspended in DCM (0.1 mL), and trifluoroacetic acid (0.12 mL, 1.6 mmol) was added thereto. After 3.5 hours at room temperature, the solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution to achieve a pH of 8. The title product was filtered and washed with water to give a white solid (298) after drying. (42 mg, 71%) LC / MS: Method 4: Rt = 1.03 min, m / z = 359.2 [MH ⁺ ].

Example 264: 1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -3- (4-methyl-6-((3- (methylamino) propyl) amino) pyrimidine -2-yl) urea (299) synthesis

Example 262 was converted to 1- (4-chloro-6-methylpyrimidin-2-yl) -3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) urea (290) and Prepared in a similar manner to Example 261 from N- (3-aminopropyl) -N-methylcarbamic acid tert-butyl ester (57 mg, 64%). LC / MS: Method 4: Rt = 1.03 min, m / z = 373.2 [MH ⁺ ].

Example 265: Synthesis of 1- (4- (tert-butyl) phenyl) -3- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) urea (301)

  Step 1: 1- (4- (tert-butyl) phenyl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (300)

  A mixture of 2-amino-4-chloro-6-methylpyrimidine (2.0 g, 14 mmol) and 4-tert-butylphenyl isocyanate (2.9 g, 16 mmol) in toluene (12.7 mL) was added at room temperature. Stir for hours and then heat at 110 ° C. overnight. After cooling, the formed slurry was filtered, washed with ether and dried to give compound (300) (2.3 g, 53%). This material was used directly in the next step.

  Step 2: 1- (4- (tert-butyl) phenyl) -3- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) urea (301)

1- (4- (tert-butyl) phenyl) -3- (4-chloro-6-methylpyrimidin-2-yl) urea (300) (100 mg, 0.30 mmol) in 2-propanol (0.5 mL) , 3- (dimethylamino) -1-propylamine (0.05 mL, 0.36 mmol) and triethylamine (0.06 mL, 0.45 mmol) were heated at 80 ° C. for 2 hours. The reaction mixture was cooled and filtered to give the title compound (301) (80 mg, 66%). LC / MS: Method 4: Rt = 1.72 min, m / z = 385.3 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 265:

Example 269: N- (3-((2- (3- (benzo [d] [1,3] dioxol-5-yl) ureido) -6-methylpyrimidin-4-yl) amino) propyl) acetamide ( 305)

1- (4-((3-Aminopropyl) amino) -6-methylpyrimidin-2-yl) -3- (benzo [d] [1,3] dioxol-5-yl in DCM (0.44 mL) ) A mixture of urea (282) (75 mg, 0.22 mmol), acetic anhydride (0.02 mL, 0.24 mmol), pyridine (0.11 mL, 1.3 mmol) and a catalytic amount of N, N-dimethylaminopyridine, Stir for 2 hours at room temperature. At this time, another portion of acetic anhydride (0.01 mL) was added and stirring was continued overnight. The mixture was diluted with DCM (3 mL) and the resulting solid was filtered and dried to give the title product (305) (39 mg, 47%). LC / MS: Method 4: Rt = 1.45 min, m / z = 387.2 [MH ⁺ ].

Example 270: Synthesis of N- {2- [2- (3-benzo [1,3] dioxol-5-yl-ureido) -6-methyl-pyrimidin-4-ylamino] -ethyl} -acetamide (306)

1- [4- (2-Amino-ethylamino) -6-methyl-pyrimidin-2-yl] -3-benzo [1,3] dioxol-5-yl-urea (283) in DCM (0.44 mL). ) (75 mg, 0.23 mmol), acetic anhydride (0.02 mL, 0.25 mmol), pyridine (0.11 mL, 1.4 mmol) and a catalytic amount of N, N-dimethylaminopyridine for 1 hour at room temperature. Stir. The mixture was diluted with DCM (3 mL) and the resulting solid was filtered and dried to give the title product (306) (63 mg, 74%). LC / MS: Method 4: Rt = 1.34 min, m / z = 373.2 [MH ⁺ ].

Example 271: N- (2- {2- [3- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -ureido] -6-methyl-pyrimidin-4-ylamino} -ethyl ) -Acetamide (307)

Example 271 was converted to 1- [4- (2-amino-ethylamino) -6-methyl-pyrimidin-2-yl] -3- (2,3-dihydro-benzo [1,4] dioxin-6-yl. ) -Urea (293) (36 mg, 43%) was prepared by a procedure similar to that described for Example 270. LC / MS: Method 4: Rt = 1.43 min, m / z = 387.2 [MH ⁺ ].

Example 272: N- (3- {2- [3- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -ureido] -6-methyl-pyrimidin-4-ylamino} -propyl ) -Acetamide (308)

Example 272 was converted to 1- [4- (3-amino-propylamino) -6-methyl-pyrimidin-2-yl] -3- (2,3-dihydro-benzo [1,4] dioxin-6-yl. ) -Urea (292) (58 mg, 69%) was prepared by a procedure similar to that described for Example 270. LC / MS: Method 4: Rt = 1.49 min, m / z = 401.2 [MH ⁺ ].

Example 273: Synthesis of N- (2- {2- [3- (4-tert-butyl-phenyl) -ureido] -6-methyl-pyrimidin-4-ylamino} -ethyl) -acetamide (309)

Example 273 was prepared according to 1- [4- (2-amino-ethylamino) -6 except that the mixture was diluted with Et ₂ O (5 mL) before filtration of the solid product (40 mg, 21%). -Methyl-pyrimidin-2-yl] -3- (4-tert-butyl-phenyl) -urea (293) was prepared by a procedure similar to that described for Example 270. LC / MS: Method 4: Rt = 2.15 min, m / z = 385.3 [MH ⁺ ].

Example 274: Synthesis of N- (3- {2- [3- (4-tert-butyl-phenyl) -ureido] -6-methyl-pyrimidin-4-ylamino} -propyl) -acetamide (310)

Example 274 was prepared according to 1- [4- (3-amino-propylamino) -6 except that the mixture was diluted with Et ₂ O (5 mL) prior to filtration of the solid product (40 mg, 21%). Prepared from -methyl-pyrimidin-2-yl] -3- (4-tert-butyl-phenyl) -urea (303) by a procedure similar to that described for Example 270. LC / MS: Method 4: Rt = 2.22 min, m / z = 399.3 [MH ⁺ ].

Example 275: N-2- (3- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -ureido) -6-methyl-pyrimidin-4-yl) -ethyl) methanesulfonamide Synthesis of (311)

1- (4-((3-Aminoethyl) amino) -6-methylpyrimidin-2-yl) -3- (3- (trifluoromethoxy) phenyl) in DCM (0.48 mL) cooled to 0 ° C. To a mixture of urea (87) (53 mg, 0.14 mmol) and triethylamine (0.04 mL, 0.28 mmol) was added methanesulfonyl chloride (0.01 mL, 0.16 mmol), which was stirred for 5 hours at room temperature. . At this time, the mixture was diluted with MeOH (5 mL) and the resulting solid was filtered. This material was purified by silica gel chromatography using a gradient of 0-10% MeOH in DCM. Evaporation of the appropriate fractions gave the title product (311) (5 mg, 7%). LC / MS: Method 4: Rt = 2.14 min, m / z = 449.1 [MH ⁺ ].

Example 276: 1- (2,3-dihydro-1H-inden-5-yl) -3- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) urea Synthesis of (313)

  Step 1: 1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (2,3-dihydro-1H-inden-5-yl) urea (312)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (1.5 g, 10 mmol) and 5-indanyl isocyanate (2.0 g, 12 mmol) in toluene (9.5 mL) was stirred for 1 hour at room temperature. And then heated at 110 ° C. overnight. After cooling, the mixture was stirred overnight. The formed slurry was filtered, washed with ether and dried to give compound (312) (2.5 g, 82%). LC / MS: Method 4: Rt = 3.79 min, m / z = 303.1 [MH ⁺ ]. This material was used directly in the next step.

  Step 2: 1- (2,3-Dihydro-1H-inden-5-yl) -3- (4-((3- (dimethylamino) propyl) amino) -6-methylpyrimidin-2-yl) urea ( 313)

1- (4-Chloro-6-methylpyrimidin-2-yl) -3- (2,3-dihydro-1H-inden-5-yl) urea (312) in 2-propanol (0.66 mL) (0 0.1 g, 0.33 mmol), 3- (dimethylamino) -1-propylamine (0.05 mL, 0.40 mmol) and triethylamine (0.07 mL, 0.5 mmol) were heated at 80 ° C. for 2 hours. . The reaction mixture was cooled and filtered to give the title compound (313) (90 mg, 70%). LC / MS: Method 4: Rt = 1.41 min, m / z = 369.3 [MH ⁺ ].

  The following examples were prepared according to a similar procedure described for Example 276:

Example 282: N- (2- {2- [3- (2,3-dihydro-1H-inden-5-yl) -ureido] -6-methyl-pyrimidin-4-ylamino} -ethyl) -acetamide ( 319)

1- [4- (2-Aminoethyl) -6-methyl-pyrimidin-2-yl] -3-(2,3-dihydro-1H-inden-5-yl) in DCM (0.38 mL) ) -Urea (316) (62 mg, 0.19 mmol), acetic anhydride (0.02 mL, 0.21 mmol), pyridine (0.10 mL, 1.2 mmol) and a catalytic amount of N, N-dimethylaminopyridine. Stir for 3 hours at room temperature. The mixture was cooled in the freezer and then diluted with diethyl ether (5 mL). The resulting solid was filtered and dried to give the title product (319) (40 mg, 57%). LC / MS: Method 4: Rt = 1.87 min, m / z = 369.2 [MH ⁺ ].

Example 283: Viability Assay for GBM4 and GBM8 Cell culture media was prepared from NSA proliferation kit (Neurocult) and NeuroCult supplement (Stemcell Tech Cat. # 05751), 10 μg / mL rh EGF 20 μL, 10 μg / mL rh LGF10 , And 10 μL of 0.2% heparin. In this medium, human glioblastoma cells were cultured in very low attachment tissue culture flasks (GBM4 and GBM8 were the tissue of these human patients until 1 × 10 ⁶ ml of cells was achieved. Are individual neurosphere cell cultures derived from GBM4 and GBM8 cells were dissociated and 10 mL of medium containing 4000 human glioblastoma cells per 90 μL was transferred to a very low binding 96 well plate and incubated overnight at 37 ° C. The next day, 10 μL of a 1% DMSO solution of the test compound in assay medium was added to the wells containing the cell suspension and the mixture was incubated at 37 ° C. for 3 days. At this time, the plate was removed from the incubator and allowed to reach room temperature. After about 30 minutes, 50 μL of Cell Titer Glo solution was added to each well and the plate was shaken at low speed for 1 minute. After 10 minutes, luminescence was recorded using a Tecan Safari2 reader.

  To determine the percentage inhibition of cell proliferation, the decrease in luminescence compared to DMSO-only control wells was used. IC50s were calculated using% inhibition of luminescence for serial dilutions of compounds fitted to a 4-parameter fit within the Prism (San Diego) curve fit program. Table 1 below shows GBM4 IC50 and GBM8 IC50 for the compounds described herein.

Example 284: Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (I) in a patient with recurrent Rb-positive glioblastoma Phase II clinical trials of compounds of V) or (VI) The purpose of this phase II clinical trial is to improve Rb-positive relapsed glioblastoma or gliosarcoma patients (no progression at 6 months) Of compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) (measured by viability) It is to determine the effect. A total of 30 patients will be treated; 15 will receive a planned surgical resection, receive the drug for 7 days before surgery, then receive the drug after recovery from surgery, and the other 15 patients Receive the drug without planned surgical procedures.

  Patients: Eligible subjects are men and women over the age of 18.

Standard:
Inclusion criteria:
• Patients with relapsed, intracranial glioblastoma or gliosarcoma as evidenced by radiographs are eligible for this protocol. Patients must have written evidence of Rb positive disease.
• All patients must sign informed consent indicating that they are aware of the nature of the study's trial. The patient must sign a permission to publish protected health information. the patient. Must be registered prior to treatment with study drug. Treatment must occur within 7 days of enrollment, and if treatment is delayed beyond 7 days, clinical tests and medical examinations for eligibility and medical history must be repeated.
Patients must have previously received external radiation and temozolomide chemotherapy, there is no limit to the number of chemotherapy used, and patients can be treated at the first, second, or third relapse .
• Patients must be> 18 years old and have a life expectancy of> 8 weeks.
• Patients must have a Karnovsky performance status of> 60.
• At enrollment, the patient must have recovered from the toxic effects of the previous treatment: eg> 28 days from any study drug [Note: off-label use of FDA-approved drugs is a study for the purposes of this protocol. Not> 28 days from previous cytotoxic therapy,> 42 days from nitrosourea,> 28 days from bevacizumab, and non-cytotoxic drugs such as interferon, tamoxifen, thalidomide, cis- > 7 days for retinoic acid and erlotinib. Inquiries related to the definition of non-cytotoxic drugs should be made directly to the Study Chain.
Patients must have sufficient bone marrow function (WBC> 3,000 / μl, ANC> 1,500 / mm ³ ,> 100,000 / mm ³ platelet count, and hemoglobin> 10 gm / dl before starting treatment. ), Sufficient liver function (SGOT and bilirubin <2 times ULN), and sufficient renal function (creatinine <1.5 mg / dL). A pre-test EKG is required for all patients and patients must have normal QT intervals. These tests must be performed within 14 days prior to registration. The appropriate level for hemoglobin can be achieved by blood transfusion.
• Patients must show clear x-ray evidence of tumor progression from MRI scans. The scan should be performed with a steroid dose that is stable within 14 days prior to enrollment and for at least 7 days. If the steroid dose is increased between the imaging date and the registration date, a new baseline MRI is required. The same type of scan, ie MRI, must be used over the duration of the protocol treatment for tumor measurement. Patients who cannot take MR images are not eligible.
• Patients who have undergone a recent resection of a recurrent or progressive tumor are eligible as long as all of the following conditions are true:
o Recovered from the effects of surgery.
o Residual lesions after resection of recurrent intracranial glioblastoma or gliosarcoma are not required for eligibility for the study. In order to optimally assess the extent of residual lesions postoperatively, MRI should be performed within 14 days before enrollment, within 96 hours within the immediate postoperative period, or at least 4 weeks postoperatively. is there. If the 96 hour scan is more than 14 days prior to registration, the scan needs to be repeated. If the steroid dose is increased between the imaging date and the registration date, a new baseline MRI is required with a stable steroid dose of at least 7 days.
• Patients must have failed previous radiation therapy and temozolomide therapy and must have a minimum of 42 days from completion of radiation therapy to study entry.
Patients who have received previous treatments including interstitial radiation therapy, stereotactic radiation, or Gliadel wafers will not have radiation necrosis based on evidence from PET scanning, MR spectroscopy or surgical documentation of the disease. Rather, a true progressive disease must be confirmed.
A subset of 15 patients will be enrolled prior to the planned surgical resection shown. Patients can enroll before surgery only if they are candidates for surgery, do not have evidence of acute intracranial hemorrhage, and can start protocol treatment in a period of 7 days before surgery .
• Reproductive patients should receive approved contraceptive methods (eg, intrauterine device [IUD], oral contraceptives, or barrier devices (for example) during study treatment and for 3 months after study treatment is discontinued. barrier device)) must be used. Women who are likely to give birth must have negative beta-HCG pregnancy test results documented within 14 days prior to enrollment.
• Tumor tissue blocks or slides from previous surgery must be available to perform IHC Rb staining. Patients with negative tumors (Rb negative) are excluded from the study.

Exclusion criteria:
• Patients must not have serious medical illnesses that, in the investigator's view, cannot be adequately controlled with appropriate treatment or impair the patient's ability to withstand this treatment.
• Patients with a history of any other cancer (except non-melanoma skin cancer or cervical intraepithelial cancer) are ineligible unless they are in complete remission and have not received all treatment for the disease for a minimum of 3 years It is.
• The patient must not have active infection or serious concurrent medical illness.
Patients with a history of acute intracranial bleeding are also excluded.
• The patient must not be pregnant / nursing and must agree to provide adequate contraception.
• The patient must not have a disease that obscures toxicity or dangerously alters drug metabolism.
Because of potential drug interactions, patients taking enzyme-induced anticonvulsants or other drugs that cause CYP3A enzyme induction or inhibition are not eligible unless they have been treated for at least 14 days .
• Patients with congenital or other reasons for extending QT interval on EKG are excluded.

  Study design: A total of 30 patients with recurrent glioblastoma or gliosarcoma were treated with formula (I), (II), (IIA), (IIB) at a daily dose of 125 mg for 21 consecutive days. , (IIC), (IID), (III), (IV), (V) or (VI) and then receive no treatment for 7 days (cycle length is 28 days). Of these 30 patients, 15 will receive the drug for 7 days prior to the indicated intended surgical resection for progression and then resume dosing at the same dose after recovery from surgery. The treatment is repeated every 28 days and in the absence of disease progression, the patient can receive 12 cycles of treatment. At that time, the patient is given the option of continuing the test past 12 cycles and up to 24 cycles.

  After registration, the available blocks or slides from the previous surgery must be submitted for diagnostic review (confirmation of glioblastoma or gliosarcoma) and determination of Rb status. Only patients with Rb positive tumors can be treated and the status of the Rb tumor must be known prior to any treatment. Additional tissue from previous surgery is also obtained to assess molecular abnormalities in the tumor. These tests are done retrospectively and do not need to be performed before enrollment.

  Monitoring includes clinical and neurological examinations before the start of each cycle (every 4 weeks). Whole blood counts with differences are examined on days 1 and 15 of each cycle. Liver and kidney functions are performed every 4 weeks. Toxicity and dose changes are based on NCI CTCAE Version 4. Disease status is assessed clinically at each cycle (every 4 weeks) and radiographically after each second cycle (every 8 weeks).

Primary endpoint:
-Effects determined by progression-free survival [Time frame: 1-2 years] [Designated as safety issue: No]
Formulas (I), (II), (IIA), (IIB) in patients with recurrent glioblastoma or gliosarcoma that are Rb-positive as measured by progression-free survival at 6 months , (IIC), (IID), (III), (IV), (V) or the effect of a compound of (VI) is determined. A total of 30 patients will be treated; 15 who will receive the planned and intended surgical resection will receive the drug for 7 days prior to surgery, then the drug after recovery from surgery, and the other 15 Human patients receive medication without planned surgical procedures.

Secondary endpoint:
• Number of participants with adverse events as a measure of safety and tolerance [Time frame: 1-2 years] [Designated as safety issue: Yes]

Example 285: Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV) in an adult with relapsed or refractory medulloblastoma ), Phase 2 clinical trial of safety and efficacy of compounds of (V) or (VI).
The purpose of this phase II clinical trial is to treat adult patients with relapsed or refractory medulloblastoma in formulas (I), (II), (IIA), (IIB), (IIC), ( It is to test how well the compounds of (IID), (III), (IV), (V) or (VI) work.

  Patients: Eligible subjects are men and women over the age of 22.

Standard:
Inclusion criteria:
• Histologically confirmed diagnosis of medulloblastoma (including posterior fossa PNET) that is recurrent, progressive, or refractory to standard treatment and for which there is no known radical treatment Patients with confirmation must be eligible, there must be evidence of measurable disease or lesion remaining in the preliminary test MRI as described fragmentarily, and patients with measurable spinal disease are eligible.
• Diagnosis should be confirmed by the institution and the tissue (from diagnosis or recurrence or preferably from both time points) should be available for biological studies.
• Patients with neurological deficits should have deficiencies that are stable for at least 1 week prior to enrollment; this is documented in the database.
・ US East Coast Cancer Clinical Trials Group (ECOG) Performance Status 0-2
• No other myelosuppressive chemotherapy or immunotherapy within 4 weeks prior to study entry (6 weeks for previous nitrosourea).
• Decadrone dose should also be stable or decreased for at least 1 week (7 days) prior to initiation of treatment.
Radiation therapy (XRT)> = 3 months before entry into the study for cranial spinal cord irradiation (> = 23 Gy);> = 8 weeks for local irradiation to the primary tumor;> = Localized symptomatic metastatic site 2 weeks before entry to the study for irradiation.
Not receiving all colony stimulating factors> = 1 week prior to study entry (GCSF, GM CSF, erythropoietin).
・ Absolute neutrophil count (ANC)> = 1000 / μL
・ Platelet count> = 50,000 / uL (unrelated to blood transfusion)
Hemoglobin> = 8.0 gm / dL (can receive RBC transfusion)
Creatinine clearance or radioisotope GFR> = 70 ml / min / 1.73 m ² or
Serum creatinine = <2.0 mg / dL
Total bilirubin = <1.5x upper limit of normal for age (ULN)
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) = <2.5 × institutional ULN
Serum glutamate oxaloacetate transaminase (SGOT) (aspartate aminotransferase [ASTM]) = <2.5 times the institutional ULN
Serum albumin> = 2.5 g / dL
• Patients must have recovered from the serious acute toxicity of all previous treatments and must meet all other eligibility criteria before entering this study.
• Pregnancy should be avoided for 12 months after the last dose for women who are likely to give birth, and women who are likely to give birth should not be pregnant or breastfeeding, Potential female patients must have negative serum or urine pregnancy test results within 24 hours prior to the start of treatment.
• Women with the possibility of childbirth are required to use two forms of acceptable contraceptive methods, including barrier methods during study participation and 12 months after the last dose, medical or personal For general reasons, 100% commitment to withdrawal is considered an acceptable form of contraception. All patients should be counseled on contraception by researchers, OB / gynecologists, or other physicians qualified in this field.
・ Signed and informed consent according to PMDA's guidelines must be obtained.

Exclusion Criteria • Clinically significant unrelated systemic disease (serious infection or prominent heart, lung, liver, or other) that may impair the patient's ability to withstand protocol treatment or interfere with the study procedure or outcome Patients with other organ dysfunction) Patients receiving other anti-cancer or investigational drug treatments Returning to follow-up visits or taking follow-up studies necessary to assess toxicity to treatment Cannot swallow-Life expectancy as determined by the treating physician <12 weeks-Cannot swallow capsules-Absorption syndrome or other symptoms that interfere with intestinal absorption-History of congestive heart failure-Need medication History of ventricular arrhythmia to be performed ・ Uncontrolled low defined as below normal lower limit for the institution despite the addition of sufficient electrolyte Calcium hyperlipidemia, hypomagnesemia, hyponatremia or hypokalemia, congenital QT syndrome

  Study Design: Patients are orally once daily on days 1-28, formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV) , (V) or (VI). Treatment is repeated every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Key outcomes:
• Response rate categorized using RECIST criteria (PR and CR) [timeframe: up to 12 months] [designated as safety issue: no]
A 95 percent confidence interval estimate of the true unknown response rate is built for each of the three layers. Confirmed complete response, partial response, and the proportion of patients with stable disease are reported descriptively for each of the three layers. A cumulative incidence function of time for objective response is also provided.

Secondary outcome:
Duration of objective response retained [timeframe: from initial scans documented for complete or partial remissions evaluated up to 12 months, documenting progression or death under study [Whichever comes first] [designated as safety issue: no]
Progression-free survival [timeframe: evaluated up to 12 months, formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), From the date of first treatment with the compound of (V) or (VI) to the document of progression under study or death, whichever comes first] [designated as a safety issue: no]
・ Medical expenses for the first 6 months after transplantation ・ Patient and graft survival

Example 286: Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or in the treatment of recurrent malignant astrocytoma Phase I / II clinical trial of safety, resistance and anti-tumor effects of compounds of (VI) This is a recurrent malignant astrocytoma (glioblastoma, gliosarcoma, anaplastic astrocytoma, poor anaplastic) (I), (II), (IIA), (IIB), (IIC), (IID), (II) in patients with glioma, anaplastic oligodendrocyte, and anaplastic ependymoma III / Phase IV clinical trial investigating the safety, resistance and antitumor effects of compounds of (III), (IV), (V) or (VI). Patients are treated for 5 maximum cycles. The treatment cycle is defined as 28 days + 7 days rest (28 + 7 days between cycles 1-4 and 28 days during cycle 5). No further cycles will begin until the treatment continuation criteria are met. Combined supportive care is allowed.

  Patients: Eligible subjects are men and women over the age of 18.

Standard:
Inclusion criteria:
• The nature of the test is communicated and written informed consent is provided.
• At least 18 years of age • ECOG performance of 0, 1, or 2 or KPS (Karnovsky Performance Status) ≧ 60.
WHO grade 4 astrocytoma (glioblastoma or gliosarcoma), or WHO grade 3 anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligodendroglial astrocytoma, or anaplastic robe Pathological evidence of cell tumor.
• Recurrent glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, or anaplasia after at least one chemotherapy and radiotherapy failure Documentation of ependymoma.
• Predict survival for at least 3 months • At least 2 weeks from tumor reduction when performed, 4 weeks from bevacizumab or other chemotherapy (6 weeks if previous chemotherapy was nitrosourea), and radiation 12 weeks after completion of therapy.
Ability to undergo MRI scanning without and using periodic imaging dyes as defined in the protocol. Formulas (I), (II), (IIA), (IIB), (IIC), (IID), At least 7 days rest of the formulation inducing CYP2C9 and CYP3A4 prior to administration of the first dose of the compound of (III), (IV), (V) or (VI) : Blood leukocyte count ≧ 3.0 × 109 / L blood absolute neutrophil count ≧ 1.5 × 109 / L blood platelet count ≧ 100 × 109 / L blood hemoglobin ≧
100 g / L (transfusion allowed) Plasma total bilirubin level ≤ 1.5 times the upper limit of the institution (ULN) in the normal (ie reference) range Plasma ASTM (aspartate aminotransferase) or ALT ≤ normal (ie reference) range 2.5 times the institutional upper limit (ULN) of plasma creatinine ≦ 1.5 times the upper institutional (ULN) range of normal (reference) range 12-lead ECG with normal follow-up; or clinically insignificant and Changes that do not require medical intervention, and QTc <500 ms Rest for at least 7 days of prescription that inhibits or induces CYP2C9 or CYP3A4 prior to the treatment date of the first study.

Exclusion criteria:
• Ongoing infection or other major or ongoing disease with unacceptable risk to the patient, according to the researcher • Grade 3 or higher constipation within the last 28 days prior to randomization or the last 14 days Grade 2 constipation within. (Patients with grade 2 constipation within the last 14 days can be re-screened if constipation decreases to ≦ grade 1 with optimal management of constipation.)
• Coexisting uncontrolled disease states, including but not limited to active heart disease and severe dementia • Hepatitis B or C or HIV infection requiring antiretroviral therapy • Other than basal cell skin cancer Active malignancies • Other active malignancies over the past 3 years • Major surgical procedures within 4 weeks • Functional neuroimaging (PET, dynamic MRI, MRS, SPECT), or recurrent tissue Previous stereotaxic or gamma knife irradiation or proton irradiation in the absence of clear progression due to reoperation with documented anatomical confirmation.
• Previous anti-tumor treatment as follows: at least 12 weeks from radiation therapy; at least 4 weeks from previous treatment with temozolomide or bevacizumab, 6 weeks from BCNU or CCNU.
• Women of reproductive age (WOCBP) who do not agree with the use of acceptable methods of contraception (oral contraceptives, IUD). For the purposes of this study, WOCBP includes women who have undergone menopause, have not undergone fallopian tube ligation, and are not postmenopausal. Postmenopausal is defined as: amenorrhea ≧ 12 consecutive months without another cause.
• Medically uncontrolled type 1 or type 2 diabetes mellitus • Pregnancy or lactation • Current participation in clinical trials of other trials within 4 weeks.
US East Coast Cancer Clinical Trials Group (ECOG) Performance Status> 2 after prescription optimization (see Appendix 4), or KPS <60
-Expected life expectancy of less than 3 months-Contraindications to study drug or known or suspected hypersensitivity-Induces or has a narrow therapeutic window, induces a sensing substrate for CYP2C9 or CYP3A4 or is a potent inhibitor thereof Patients who must take concomitant medications should not participate.
Lack of relevance to participation in clinical trials for any reason as determined by the researcher

Study design:
Clinical trials are divided into two phases. In the first phase, 10-20 patients are enrolled and for 28 days, 300-520 mg BID of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III ), (IV), (V) or (VI) is treated twice daily (BID). Phase 1 primary endpoints are patients with recurrent or progressive glioblastoma of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), Determining the recommended second phase dose (RP2D) of a compound of (IV), (V) or (VI) and formula (I), (II), (IIA), ( IIB), (IIC), (IID), (III), (IV), (V) or (VI) to evaluate the safety and toxicity of a compound. The study has a 3 + 3 design and the first cohort is 400 mg of formula (I), (II), (IIA), (IIB), (IIC), (IID), (twice daily for 28 days) Treated with compounds of III), (IV), (V) or (VI) and repeated up to 5 cycles. If dose limiting toxicity (DLT) occurs, such as neutropenia, dosing is interrupted and individual patients are resumed at the same or lower dosage levels following normal procedures after normalization. Two or three of the first three patients at a particular dose level have the formula (I), (II), (IIA), (IIB), (IIC), (IID), ( When receiving DLT during the first 28 days of treatment with a compound of III), (IV), (V) or (VI), the following patients are treated at lower dosage levels. If a single DLT occurs during the first 28 days of dosing in the first 3 patients, another 3 patients are treated at the same dosage level. If 2 out of 6 patients exhibit DLT, the next patient is treated at a lower dose level. The highest dose level without DLT or with a maximum of 1 DLT out of 6 patients is the recommended Phase 2 dose (RPTD). All assessments regarding dose adjustment for subsequent cohorts will be performed during the first 28 days of treatment. Patients who have not progressed can be treated for a total of 5 28-day cycles (24 weeks).

  In the second phase, 12 patients were enrolled and identified for 28 days for the identified RP2D formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), Treated with a compound of (IV), (V) or (VI) and repeated in 5 cycles. The primary endpoint of Phase 2 is to assess the proportion of patients who do not progress at 24 weeks and formulas (I), (II), (IIA), (IIB), (IIC), (IID), To evaluate the safety, tolerance and adverse event profile of a compound of (III), (IV), (V) or (VI).

Key outcomes:
• Phase 1—Determine the recommended Phase 2 dose. [Time frame: 8 months] [Designated as safety issue: yes]
• Phase 2—Determine anti-tumor effect [Time frame: 4 months] [Designated as safety issue: yes]
• Phase 1-Number of participants with adverse events as safety and tolerance measures [timeframe: 6 months] [designated as safety issue: yes]
• Physical / neurological examination (pathological findings and quality and quantity).
Adverse events (quality and dose per dose level)
Vital signs, ECG, laboratory parameters (pathological findings as quality and quantity for laboratory parameters, descriptive statistics)

Secondary outcome:
• Stage I nephropathy-maximum tolerated dose (MTD) [time frame: 8 months] [designated as safety issue: yes]
The MTD of the compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) is identified.
Phase 1-Optimal response molecular marker [timeframe: 8 months] [designated as safety issue: yes]
Evaluate potential molecular markers that can predict optimal response subpopulations Phase 1-IGF (insulin-like growth factor) -1R pathway molecular marker [timeframe: 8 months] [designated as a safety issue T: Yes]
Of the formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) in a patient with malignant astrocytoma Substitute molecular markers for activation / inhibition of the IGF-1R pathway are evaluated after treatment with compounds
Phase 2-Tumor growth arrest time (TTP) and overall survival (OS) [Time frame: 4 months] [Designated as safety issue: yes]
Tumor growth in patients treated with compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) Determine stop time (TTP) and overall survival (OS)
-Phase 2-Response rate [Time frame: 4 months] [Designated as safety issue: yes]
Relapsed malignant stars after treatment with a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) Assessing response rate (ORR) in astrocytoma Phase 2-Image evidence of reaction. [Time frame: 4 months] [Designated as safety issue: yes]
Substitution of reactions on MRI (magnetic resonance imaging) sequences with RANO criteria (with additional special attention to T2-FLAIR, DWI (diffusion weighted imaging), perfusion MRI and multi-voxel MRS (magnetic resonance spectroscopy) sequences) Identify image evidence.

Example 287: Pharmaceutical Composition Example 287A: Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of formula (I), (II), (IIA), (IIB) , (IIC), (IID), (III), (IV), (V) or (VI) are dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a unit dosage form suitable for administration by injection.

  In another embodiment, the following ingredients are mixed to form an injectable formulation:

  Combine all of the above ingredients except water, stir and heat slightly if necessary. A sufficient amount of water is then added.

Example 287B: Oral Composition To prepare a pharmaceutical composition for oral delivery, 100 mg of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III) , (IV), (V) or (VI) is mixed with 750 mg starch. The mixture is incorporated into an oral dosage form such as a hard gelatin capsule suitable for oral administration.

  In another embodiment, the following ingredients are intimately mixed and pressed into a single split tablet.

  In yet another embodiment, the following ingredients are intimately mixed and filled into hard shell gelatin capsules.

  In yet another embodiment, the following ingredients are mixed to form a solution / suspension for oral administration:

Example 287C: Sublingual (hard lozenge) composition To prepare a pharmaceutical composition for buccal delivery such as hard lozenges, 100 mg of formula (I), (II), (IIA), (IIB) , (IIC), (IID), (III), (IV), (V) or (VI) with 1.6 mL light corn syrup, 2.4 mL distilled water, and 0.42 mL mint Mix with 420 mg powdered sugar mixed with the extract. The mixture is slowly blended and poured into a mold to form a lozenge suitable for buccal administration.

Example 287D: Inhalation Composition To prepare a pharmaceutical composition for inhalation delivery, 20 mg of formula (I), (II), (IIA), (IIB), (IIC), (IID), ( III), (IV), (V) or (VI) compound is mixed with 50 mg anhydrous citric acid and 100 mL 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit such as a nebulizer suitable for inhalation administration.

Example 287E: Rectal Gel Composition To prepare a pharmaceutical composition for rectal delivery, 100 mg of formula (I), (II), (IIA), (IIB), (IIC), (IID), A compound of (III), (IV), (V) or (VI) is mixed with 2.5 g methylcellulose (1500 mPa), 100 mg methylparaben, 5 g glycerin and 100 mL pure water. The resulting gel mixture is then incorporated into a rectal delivery unit such as a syringe suitable for rectal administration.

Example 287F: Suppository Formulation A compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) A suppository with a total weight of 2.5 g was prepared by mixing with Witepsol® H-15 (triglycerides of saturated plant fatty acids; Riches-Nelson, Inc., New York) with the following composition: have:

Example 287G: Topical Gel Composition To prepare a pharmaceutical topical gel composition, 100 mg of Formula (I), (II), (IIA), (IIB), (IIC), (IID), A compound of (III), (IV), (V) or (VI) is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into a container such as a tube suitable for topical administration.

Example 287H: Ophthalmic Solution Composition To prepare a pharmaceutical ophthalmic solution composition, 100 mg of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III ), (IV), (V) or (VI) compound is mixed with 0.9 g NaCl in 100 mL pure water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into an eye drop delivery unit such as an eye drop container suitable for eye drops.

  The examples and embodiments described herein are for illustrative purposes only and, in some embodiments, various modifications or changes are intended to be included within the scope of the disclosure and the appended claims. .

Claims (116)

A compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof,
Where
A is a single bond, O, or N (R ₁₀ );
X, Y, and Z are each independently N or C (R ₇ ), and at least one of X, Y, and Z is N;
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ ,-(C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ), or
And
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
J is C (H) or N;
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
Each R ₇ is independently H, halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H, or unsubstituted C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-5,
p is 1-3;
A compound wherein q is 1-3. R ₂ and _{R 3} are each independently, H, _-CN, C 1 -C _{4 alkyl,} C 3 -C ₆ cycloalkyl, or _C 2 -C ₇ heterocycloalkyl, compounds of claim 1 . The compound according to claim 2, wherein R ₂ and R ₃ are each H. The compound according to claim 1, wherein R ₂ and R ₃ are combined to form a 5- or 6-membered heterocycle. The compound according to claim 4, wherein R ₂ and R ₃ are combined to form a 5-membered heterocyclic ring. R ₆ is _C 2 -C ₇ heteroaryl, substituted or unsubstituted, A compound according to any one of claims 1-5. R ₆ is a substituted or unsubstituted pyridyl, a compound according to claim 6. R ₆ is unsubstituted pyridyl compound according to claim 7. R ₆ is
The compound according to any one of claims 1 to 5, wherein The compound according to claim 9, wherein R ₁₃ is H. R ₁₃ is _C 1 -C ₆ alkyl substituted or unsubstituted, A compound according to claim 9. R ₁₃ is -CH _3, The compound according to claim 11. R ₁₃ is _-CH 2 CH _3, The compound according to claim 11.   14. A compound according to any one of claims 9-13, wherein J is C (H).   15. A compound according to claim 14, wherein p is 2 and q is 1.   15. A compound according to claim 14, wherein p is 3 and q is 1.   15. A compound according to claim 14, wherein p is 2 and q is 2.   14. A compound according to any one of claims 9-13, wherein J is N.   19. A compound according to claim 18 wherein p is 2 and q is 2. R ₆ is _C 2 -C ₇ heterocycloalkyl substituted or unsubstituted, A compound according to any one of claims 1-5. R ₆ is morpholinyl, substituted or unsubstituted, A compound according to claim 20. R ₆ is a substituted or unsubstituted piperidinyl, A compound according to claim 20. R ₆ is _{- (C (R 14) (} R 15)) is a _{m R 21,} The compound according to any one of claims 1-5. R ₂₁ is -OH, A compound according to claim 23. R ₆ is _{- (C (R 14) (} R 15)) is a _{m N (R 11) (R} 12), A compound according to any one of claims 1-5. R ₁₁ and _{R 12} is CH _3, respectively, a compound of claim 25. R ₁₄ and _{R 15} are each H, A compound according to any one of claims 23-26.   28. A compound according to any one of claims 23 to 27, wherein m is 2.   28. A compound according to any one of claims 23 to 27, wherein m is 3. 30. A compound according to any one of claims 1-29, wherein A is N (R < ₁₀ >). R ₁₀ is H or CH _3, The compound of claim 30.   30. The compound according to any one of claims 1-29, wherein A is O.   30. The compound according to any one of claims 1-29, wherein A is a single bond. R ₅ is _C 1 -C ₆ alkyl substituted or unsubstituted, A compound according to any one of claims 1-33. R ₅ is CH _3, A compound according to claim 34. R ₅ is _CH 2 CH _3, The compound of claim 34.   37. The compound according to any one of claims 1-36, wherein n is 2.   37. The compound according to any one of claims 1-36, wherein n is 1.   37. The compound according to any one of claims 1-36, wherein n is 0. Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or Unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, a compound according to any one of claims 1-38. 41. Each R ₁ is independently halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted C ₁ -C ₆ alkoxy. Compound described in 1. Two R ₁ together form a substituted or unsubstituted heterocyclic ring, or form a substituted or unsubstituted carbocyclic compound according to any one of claims 1-37. 43. The compound according to any one of claims 1-42, wherein X is C (R) ₇ , Y is N, and Z is N. 43. The compound of any one of claims 1-42, wherein X is C (R) ₇ , Y is C (R) ₇ , and Z is N. 43. The compound of any one of claims 1-42, wherein X is C (R) ₇ , Y is N, and Z is C (R) ₇ . 43. The compound according to any one of claims 1-42, wherein X is C (R) ₇ , Y is C (R) ₇ , and Z is C (R) ₇ . R ₇ is H, A compound according to any one of claims 1-46. A compound of formula (II), or a pharmaceutically acceptable salt, solvate or prodrug thereof,
Where
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , or
And
J is C (H),
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C, ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H, or unsubstituted C ₁ -C ₄ alkyl;
m is 2-6,
n is 0-5,
p is 1-3;
A compound wherein q is 1-3. Independently R ₂ and _{R 3} are _{each, H, -CN, C 1 -C} 4 _alkyl, C 3 -C ₆ cycloalkyl, or _C 2 -C ₇ heterocycloalkyl, A compound according to claim 48 . R ₂ and _{R 3} are each H, A compound according to claim 49. R ₂ and R ₃ together form a 5- or 6-membered heterocyclic ring compound of claim 48. Is R ₂ and R ₃ are integrally form a 5-membered heterocyclic compound of claim 51. R ₆ is _{- (C (R 14) (} R 15)) is a _{m R 21,} The compound according to any one of claims 48-52. R ₂₁ is —OH, —N (R ₂₂ ) S (═O) ₂ R ₂₃ , —CO ₂ R ₂₂ , —C (═O) N (R ₂₂ ) ₂ , —N (R ₂₂ ) C (═O ) _{R 23,} substituted or unsubstituted _C 1 -C ₆ alkoxy, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, a compound according to any one of claims 48-53. R ₂₁ is -OH, A compound according to claim 54. R ₂₁ is _{-N (R 22) S (=} O) 2 R 23, The compound according to claim 54. R ₂₁ is _{-N (R 22) C (=} O) R 23, The compound according to claim 54. R ₂₁ is substituted or unsubstituted _C 1 -C ₆ alkoxy, A compound according to claim 54. R ₂₁ is _C 2 -C ₇ heteroaryl, substituted or unsubstituted, A compound according to claim 54. And R ₂₂ are each independently H or unsubstituted _C 1 -C ₆ alkyl, _{and, R 23} is _C 1 -C ₆ alkyl unsubstituted any one of claims 48-59 Compound described in 1. And R ₁₄ and _{R 15} are each independently, H, or is _C 1 -C ₆ alkyl substituted or unsubstituted, A compound according to any one of claims 48-60. R ₁₄ and _{R 15} are each H, A compound according to any one of claims 48-60.   63. The compound according to any one of claims 48-62, wherein m is 2.   63. A compound according to any one of claims 48-62, wherein m is 3. R ₆ is _C 2 -C ₇ heteroaryl, substituted or unsubstituted, A compound according to any one of claims 48-52. R ₆ is a substituted or unsubstituted pyridyl, a compound according to claim 65. R ₆ is _C 2 -C ₇ heterocycloalkyl substituted or unsubstituted, A compound according to any one of claims 48-52. R ₆ is morpholinyl, substituted or unsubstituted, A compound according to claim 67. R ₆ is a substituted or unsubstituted piperidinyl, A compound according to claim 67. R ₁₀ is H or CH _3, The compound according to any one of claims 48-69. A compound of formula (IIA), or a pharmaceutically acceptable salt, solvate or prodrug thereof,
Where
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (═O) _2. R ₉ , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO ₂ R ₈ , _{-N (R 8) 2, -C} (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted Substituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, Or, two R ₁ s together, form a substituted or unsubstituted heterocyclic or substituted or unsubstituted ring carbon,
R ₂ and R ₃ are each independently H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₂ -C ₇ heterocycloalkyl, or R ₂ and R ₃ Together form a 5- or 6-membered heterocycle,
R ₄ is H, halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —SR ₈ , —N (R ₈ ) S (═O) ₂ R _9. , S (═O) ₂ N (R ₈ ) ₂ , —S (═O) R ₉ , —S (═O) ₂ R ₉ , —C (═O) R ₉ , —CO ₂ R ₈ , —N (R ₈ ) ₂ , —C (═O) N (R ₈ ) ₂ , —N (R ₈ ) C (═O) R ₉ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl substituted, or a substituted or unsubstituted _C 2 -C ₇ heteroaryl, or 2 The of R ₁ together, a substituted or unsubstituted heterocyclic ring, or form a substituted or unsubstituted carbocyclic ring, wherein, when n is 0, R ₄ is not a halogen,
R ₅ is halogen, —CN, —OH, —CF ₃ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C _6. heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl, substituted or unsubstituted _C 3 -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _{C 2,} a -C ₇ heteroaryl,
R ₆ is — (C (R ₁₄ ) (R ₁₅ )) _m N (R ₁₁ ) (R ₁₂ ),
R ₁₁ and R ₁₂ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₁ and R ₁₂ together are 5, 6, 7, or 8 members. Form a heterocycle of
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl, or R ₁₄ and R ₁₅ together are 4, 5, 6 membered cycloalkyl. Forming a ring,
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H or C ₁ -C ₄ alkyl;
m is 2-6,
A compound wherein n is 0-4. Independently R ₂ and _{R 3} are _{each, H, -CN, C 1 -C} 4 _alkyl, C 3 -C ₆ cycloalkyl, or _C 2 -C ₇ heterocycloalkyl, A compound according to claim 71 . R ₂ and _{R 3} are each H, A compound according to claim 72. R ₂ and R ₃ together form a 5- or 6-membered heterocyclic ring compound of claim 71. Is R ₂ and R ₃ are integrally form a 5-membered heterocyclic compound according to claim 74. R ₆ is _- a _{(C (R 14) (R} 15)) m N (R 11) (R 12), R 14 and _{R 15} are each H, in any one of claims 71-75 The described compound. And R ₁₁ and _{R 12} are each independently H or substituted or unsubstituted _C 1 -C ₆ alkyl, The compound of claim 76. And R ₁₁ and _{R 12} are each independently _C 1 -C ₆ alkyl unsubstituted compound of claim 77. R ₁₁ and _{R 12} are -CH _3, respectively, a compound of claim 78.   80. The compound according to any one of claims 71 to 79, wherein m is 2.   80. The compound according to any one of claims 71 to 79, wherein m is 3. R ₁₀ is H or CH _3, The compound according to any one of claims 71-81.   83. The compound according to any one of claims 71 to 82, wherein n is 0.   83. The compound according to any one of claims 71 to 82, wherein n is 1. A compound of formula (VI), or a pharmaceutically acceptable salt, solvate or prodrug thereof,
Where
Each R ₁ is independently halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₈ , —N (R ₈ ) S ( _{= O) 2 R 9, S} (= O) 2 N (R 8) 2, -S (= O) R 9, -S (= O) 2 R 9, -C (= O) R 9, -CO _{2 R 8, -N (R 8} ) 2, -C (= O) N (R 8) 2, -N (R 8) C (= O) R 9, substituted or unsubstituted _C 1 -C ₆ alkyl Substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted _C 6 _{-C 10} aryl, or substituted or unsubstituted _C 2 -C ₇ heteroarylene, Or two R ₁ together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted cyclic carbon;
R ₂ and R ₃ are each independently H or C ₁ -C ₄ alkyl, or R ₂ and R ₃ together form a 5- or 6-membered heterocycle,
R ₅ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₆ is unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₂ -C ₇ heteroaryl, — (C (R ₁₄ ) (R ₁₅ )) _m R ₂₁ , or
And
J is C (H),
R ₁₃ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted -C a ₁ -C ₄ alkyl _C 6 _{-C 10} aryl, or substituted or unsubstituted _-C 1 -C ₄ alkyl _C 2 -C ₇ heteroaryl,
R ₁₄ and R ₁₅ are each independently H, halogen, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₁ is halogen, —CN, —NO ₂ , —OH, —OCF ₃ , —OCH ₂ F, —OCF ₂ H, —CF ₃ , —SR ₂₂ , —N (R ₂₂ ) S (═O) _{2. R 23, -S (= O)} 2 N (R 22) 2, -S (= O) R 23, -S (= O) 2 R 23, -C (= O) R 23, -CO 2 R 22 _{, -C (= O) N (} R 22) 2, -N (R 22) C (= O) R 23, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 2 -C ₇ heterocycloalkyl or substituted or unsubstituted _C 2 -C ₇ heteroaryl,
Each R ₂₂ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₂₃ is a substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ₈ is independently H, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₉ is substituted or unsubstituted C ₁ -C ₆ alkyl;
R ₁₀ is H;
m is 2-6,
n is 0-5,
p is 1-3;
A compound wherein q is 1-3. R ₂ and _{R 3} are each independently H or _C 1 -C ₄ alkyl, A compound according to claim 85. R ₂ and _{R 3} are each H, A compound according to claim 86. R ₂ and R ₃ together form a 5- or 6-membered heterocyclic ring compound of claim 85. Is R ₂ and R ₃ are integrally form a 5-membered heterocyclic compound of claim 88. R ₆ is _{- (C (R 14) (} R 15)) is a _{m R 21,} The compound according to any one of claims 85-89. Independently R ₁₄ and _{R 15} are each, H, halogen or unsubstituted _C 1 -C ₆ alkyl, A compound according to any one of claims 85-90. R ₁₄ and _{R 15} are each H, A compound according to any one of claims 85-90. R ₂₁ is —OH, —N (R ₂₂ ) S (═O) ₂ R ₂₃ , —CO ₂ R ₂₂ , —C (═O) N (R ₂₂ ) ₂ , —N (R ₂₂ ) C (═O ) _{R 23,} substituted or unsubstituted _C 1 -C ₆ alkoxy, or substituted or unsubstituted _C 2 -C ₇ heteroaryl, a compound according to any one of claims 85-92. R ₂₁ is -OH, A compound according to claim 93. R ₂₁ is _{-N (R 22) S (=} O) 2 R 23, The compound according to claim 93. R ₂₁ is _{-N (R 22) C (=} O) R 23, The compound according to claim 93. R ₂₁ is substituted or unsubstituted _C 1 -C ₆ alkoxy, A compound according to claim 93. R ₂₁ is _C 2 -C ₇ heteroaryl, substituted or unsubstituted, A compound according to claim 93. R ₂₂ are each independently H or unsubstituted _C 1 -C ₆ alkyl, _{and, R 23} is _C 1 -C ₆ alkyl unsubstituted, in any one of claims 85-98 The described compound.   99. The compound according to any one of claims 85-99, wherein m is 2.   99. The compound according to any one of claims 85-99, wherein m is 3. R ₆ is
90. The compound of any one of claims 85-89, wherein R ₆ is
90. The compound of any one of claims 85-89, wherein R ₁₃ is H or unsubstituted _C 1 -C ₆ alkyl, A compound according to claim 102 or 103. And R ₁ are each independently _halogen, -OCF 3, -CF _3, an unsubstituted _C 1 -C ₆ alkyl or unsubstituted _C 1 -C ₆ alkoxy, or any of claims 85-104 1 Compounds described in 1. And R ₁ are each independently a halogen, a compound according to any one of claims 85-104.   107. The compound according to any one of claims 85-106, wherein n is 1.   107. The compound according to any one of claims 85-106, wherein n is 2.   105. The compound according to any one of claims 85-104, wherein n is 0. A compound having a structure selected from the following, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  112. A compound according to any one of claims 1-110, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and at least one pharmaceutically acceptable excipient, Pharmaceutical composition.   120. A disease in a subject comprising administering a compound comprising the compound of claim 1-110, or a pharmaceutically acceptable salt, solvate, or prodrug thereof to a subject in need thereof. Wherein the disease is cancer or Down's syndrome.   113. The method of claim 112, wherein the disease is cancer.   The cancer is brain cancer, glioblastoma multiforme, medulloblastoma, astrocytoma, brainstem glioma, meningioma, oligodendroma, melanoma, lung cancer, breast cancer, or leukemia 114. The method according to 113.   113. The method of claim 112, wherein the disease is Down syndrome.   110. A method of inhibiting the activity of Olig2 in a cell, comprising the step of adding to a compound according to any one of claims 1-110, or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a cell. A method comprising the step of contacting.